selectin inhibitors: a patent review

1. Introduction

2. Modulation of selectin activity

by inhibition of selectin--ligand

interaction


by inhibition of selectin

expression


by ligand cleavage

5. Conclusion

6. Expert opinion

Review

Selectin inhibitors: a patentreviewPatricia W Bedard† & Neelu Kaila§†Pfizer, 200 CambridgePark Drive, Cambridge, MA 02140, USA

Importance of the field: Selectins play a significant and well-documented role

in inflammation and immune response. They initiate tethering and rolling of

blood borne leukocytes leading to their activation, adhesion and subsequent

extravazation into tissues. This is important for healthy immune response and

tissue repair. However, dysregulation of selectins leads to exacerbation of

disease. Atherosclerosis, restenosis, deep venous thrombosis and tumor

metastasis are just a few of the diseases in which selectin blockade has been

demonstrated to ameliorate disease pathology. Thus, selectins remain

attractive targets for amelioration of disease.

Areas covered in this review: Summarized here are new patents/patent appli-

cations on selectin inhibition published since our last review in 2003 and any

significant changes or progress made in demonstrating clinical safety and effi-

cacy of therapeutics covered by patents/patent applications reviewed in 2003.

What the reader will gain: A comprehensive review of new developments in

the field of selectin inhibition through discussion of patents/patent applica-

tions from 2003 to August 2009, reports on clinical results where available

and selected literature.

Take home message: The field of selectin inhibition has matured significantly

in recent years in the ability to inhibit selectin/ligand interactions with

drug-like molecules and to demonstrate disease modification in human trials.

Keywords: adhesion molecules, inflammation, selectins, vascular disease

Expert Opin. Ther. Patents (2010) 20(6):781-793

1. Introduction

The selectins are a family of cell surface glycoproteins known as C-type lectins fortheir calcium-dependent carbohydrate binding activity. Three members have beenidentified, P-, E- and L-selectins (Figure 1A). P-selectin is found on activated plate-lets and vascular endothelium (Figure 2). It is the first selectin to be expressed duringinflammation. Pre-stored in a-granules of platelets and Weibel Palade bodies ofendothelial cells, P-selectin is translocated to the cell surface within minutes ofinflammatory stimulus [1]. E-selectin is expressed on endothelial cells after de novosynthesis, within a few hours of activation [1]. L-selectin is expressed on lympho-cytes, functioning as a homing receptor, mediating binding of lymphocytes tohigh endothelial venules of peripheral lymph nodes [1].

The selectins consist of an N-terminal lectin-like domain, an EGF-like domain, avariable number of repeated regions bearing homology to complement binding pro-teins and a cytoplasmic tail (Figure 1A). The X-ray crystal structures of P- andE-selectins have been solved, as have the domains necessary for ligand binding [2,3].All three selectins possess a calcium ligated binding site that recognizes the carbohy-drate epitope, sialyl Lewisx (sLex) (Figure 1C). Binding of sLex by selectins is of lowaffinity which contributes to the fast on and off rate binding necessary for the charac-teristic rolling of leukoctes on inflamed endothelium. In addition to the sLex bindingsite, P- and L-selectins have been shown to also utilize a binding domain consisting of

10.1517/13543771003767468 © 2010 Informa UK Ltd ISSN 1354-3776 781All rights reserved: reproduction in whole or in part not permitted

Exp

ert O

pin.

The

r. P

aten

ts D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Sydn

ey o

n 09

/02/

14Fo

r pe

rson

al u

se o

nly.

three sulfated tyrosines [4]. The crystal structure of P-selectinbinding its primary ligand, P-selectin glycoprotein-1 (PSGL-1)(Figure 1B), showed yet a third region of binding contacts, ahydrophobic series of residues. This triad of weak interactionsworks cooperatively to cause higher affinity binding betweenPSGL-1 and P-selectin than sLex alone [3].Numerous studies involving ablation of one or more of the

selectins in mice, injury models, and disease models in higheranimals and in humans have demonstrated the important roleselectins play in diseases with an inflammatory and/or immunecomponent. We refer readers to several reviews [5-8] for moreinformation on the various diseases and elaborated or proposedmechanisms that have laid the foundation for this field. Basedon the significant body of research that exists, the selectinsremain an attractive target for amelioration of a host of diseasesand we focus here on recent progress made in developingselectin inhibitors. Specifically, we summarize patents/patentapplications published since our 2003 review and updateclinical findings on therapeutics already reviewed in 2003.

2. Modulation of selectin activity byinhibition of selectin--ligand interaction

By far the most common approach in inhibiting selectin func-tion is by direct inhibition of one or more of the selectins. Theselectins’ mediation of leukocyte rolling on inflamed vascularendothelium offers a clear mechanism to model and measureinhibition of receptor ligand binding. Primary strategies todate include carbohydrate molecules, carbohydrate mimetics,non-carbohydrate small and high molecular mass molecules,peptides, antibodies and aptamers (nucleotides).

2.1 Carbohydrate-based inhibitorsAll three selectins recognize and bind to epitopes containingthe carbohydrate sLex, generally presented by a cell surface

glycoprotein or glycolipid. Although the use of native sLex

alone proved unsuccessful as a therapeutic [9], carbohydrate-based drugs remain a viable strategy. This approach strivesto maintain or increase desirable biological activity of nativecarbohydrates while removing any potentially undesirableactivity (such as anticoagulation of heparins) and improvingpharmacokinetics through rational drug design.

The University of California (UC) researchers havedescribed in vitro and in vivomethods for identifying heparinsand heparinoids that modulate the activity of selectins. Thedescription further states that these heparin formulationshave the potential to mediate hematogenous metastasis inaddition to inflammatory diseases, ischemia-reperfusioninjury and sickle cell anemia [10]. Heparin is a known inhibi-tor of selectin-mediated interactions. UC researchers built onthis known activity. Using P- and L-selectin deficient mice(PL-/-) in an experimental metastasis model, they showedimproved survival and reduced metastasis in the doubleknockout mice, and in wild-type mice treated with unfractio-nated heparin (UFH) or a non-anticoagulant (NAC) heparinderivative. NAC reduced the number of metastatic foci morethan UFH in wild-type mice and was comparable to thereduction seen in PL-/- mice. Treatment of the PL-/- micewith a NAC did not further affect metastasis rates; however,UFH treatment reduced metastasis rates further [11]. The exactderivative used is not specified; however, characterization ofseveral 2-O-desulfated, 6-O-desulfated, N-acetylated H anda glycol split H combinations are described in a previouspaper published by this group [12]. For a thorough review ofthe anti-inflammatory, anti-metastatic and anti-coagulantstructure function relationships and adverse events of variousheparin preparations see [13].

ParinGenix (USA) has used a similar approach in attemp-ting to maximize the anti-selectin activity of heparin, whileminimizing the anti-coagulant effect. They have shown that2-O, 3-O desulfated heparin (ODSH or PGX-100) can blockP-selectin-mediated A375 human melanoma cell adhesionand that the desulfation modification reduces potentiallydose-limiting anti-coagulant effects [14]. Intravenously admin-istered PGX-100 was in Phase II for cardiac ischemia reperfu-sion injury (IRI) [15]. Our searches did not result in any recentpatent applications or yield any results of this trial. However,the company reportedly conducted a Phase IIb in chronicobstructive pulmonary disease (COPD). This trial has beenterminated due to interim analysis results showing evidenceof safety without efficacy of ODSH in patients with acuteexacerbation of COPD [16]. ParinGenix was also investigatingPGX-200, an inhaled formulation of ODSH. There is nofurther reported development of an inhaled formulation.

Researchers at GlycoMimetics (founded in part by acquisi-tion of GlycoTech) have filed patent applications relating toa series of benzyl amino sulfonic acid (BASA)-basedcompounds as pan selectin inhibitors (Figure 3). They broadlydescribe inflammatory and immune diseases and morespecifically sickle cell, T-cell lymphoma and transplant

Article highlights.

• Selectin inhibition remains an attractive target foramelioration of a host of inflammatory diseases.

• Direct inhibition of selectin--ligand interaction is the mostwidely used approach, encompassing the use ofcarbohydrate molecules, carbohydrate mimetics,non-carbohydrate small and high molecular massmolecules, peptides, antibodies and aptamers(nucleotides).

• Clinical safety and efficacy in Phase I and II have beendemonstrated by small molecule and recombinantprotein approaches to direct inhibition.

• Modulation of selectin expression has beendemonstrated with non-carbohydrate small moleculesand aptamers.

• Proteolytic cleavage of selectin ligand, P-selectinglycoprotein-1, by a metalloproteinase inhibits P-selectinactivity in vitro.

This box summarizes key points contained in the article.

Selectin inhibitors: a patent review

782 Expert Opin. Ther. Patents (2010) 20(6)

Exp

ert O

pin.

The

r. P

aten

ts D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Sydn

ey o

n 09

/02/

14Fo

r pe

rson

al u

se o

nly.

rejection. In this class of compounds, BASAs are linked to aselectin binding carbohydrate or glycomimetic. The carbohy-drate moiety could be sLex or an sLex-isomer, sialyl-Lewisa.Several different linkers have been used between the BASAsand carbohydrate moiety [17,18]. In vivo data have beenincluded for some of the compounds. A cyclobutene-dione containing, sLex--BASA analogue (3.1) has shownreduction in neutrophils when dosed intraperitoneally at1 mg/kg in the thioglycollate-induced peritonitis (TIP)model [19]. Two analogues (3.2) and (3.3) belonging to theglycomimetic-BASA series have shown activity in a mouseair pouch model when given intravenously (i.v.) [20]. In oneof the publications, the GlycoMimetic group has replacedthe BASA group with benzyl amino carboxylic acid (BACA),heterocycles or orotic acid. In some instances, the inhibitoris pegalated or PEG is used as a linker of the two components.These compounds inhibited IL-1b-induced rolling in themouse mesenteric vessels when dosed i.v. at 50 mg/kg. Theglycomimetic moiety is reportedly sufficient for modifyingE-selectin activity, whereas the BASA and BACA groupsprovide the additional P- and L-selectin binding functionality.

This group have described composition and use of pseudo-oligosaccharide cyclohexane derivatives for treatment ofvascular dysfunction and abnormalities [21,22]. In vivo data

for one analogue (3.4) have been reported. Compound (3.4)when administered i.v. to stimulated sickle cell mice decreasedthe number of adherent leukocytes on the endothelium,reduced the number of sickled red blood cells adhering to leu-kocytes, as well as prolonged survival of sickle cell mice afterinduction of vaso-occlusion by TNF-a administration. Inaddition, compound (3.4) inhibited rolling leukocyte flux inleptin receptor deficient, db/db mice, which are a mousemodel of type 2 diabetes mellitus. Substitution of sialic acidhexose ring with cyclohexane decreases P-selectin activity ofthese inhibitors as assessed by E- or P-selectin plate-basedbinding assays and a mouse neutrophil migration assay.

Finally, GlycoMimetics has completed two Phase Iclinical studies of lead compound, GMI-1070, a syntheticglycomimetic molecule and a pan-selectin inhibitor. A PhaseI/II trial was planned in 2009 for vaso-occlusive crisis ofsickle cell disease [23]. GMI-1070 has been shown to reduceadherent leukocytes and improve blood flow rate in asickle cell mouse model [24]. It is also in preclinical evalua-tion for use in combination with cancer chemotherapy toprevent selectin-mediated cancer cell adhesion (companywebsite communication).

Bimosiamose (TBC 1269), a mannose-based dimer(Figure 4) [25], was in Phase II for treatment of asthma

L-selectin: Constitutive onleukocytes, amplifies recruitmentvia leukocyte-leukocyte interactions,mediates lymphocyte homing.

E-selectin: Inducible (h)on endothelial cells, mediatesslow rolling as a prerequisite forfirm attachment.

P-selectin: Inducible (min)on endothelial cells and platelets,mediates initial attachment ofleukocytes.

Cyto CRs EGF Lectin

Ligand binding domains

The selectins Ligands

Sulfated tyrosinesO-linked glycans

PSGL-1

O OO

O

O

O

O

OH

OH OHOH

OH

OH

OH

OH

OH

HO

HO

NHAc

HO

HO

AcHN

sLex

C.

B.A.

Figure 1. Selectins and two important ligands. The selectins consist of an N-terminal lectin-like domain an EGF-like domain,

a variable number of repeated regions bearing homology to complement binding proteins (CRs) and a cytoplasmic tail.

Bedard & Kaila

Expert Opin. Ther. Patents (2010) 20(6) 783

Exp

ert O

pin.

The

r. P

aten

ts D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Sydn

ey o

n 09

/02/

14Fo

r pe

rson

al u

se o

nly.

(inhaled), reperfusion injury (injectible) and psoriasis (topi-cal) at the time of our last report. There was an additionalinhaled version of TBC 1269 in preclinical investigation forasthma. Since that time, Texas Biotech the original assigneewas bought by Encysive (now a wholly owned subsidiary ofPfizer). Revotar Ag (Germany) under a license from Encysiveis continuing development of an inhaled version of TBC1269 for asthma and COPD and a cream and subcutaneousadministration for psoriasis. Published data show efficacy ina human allergen challenge model of asthma. Late allergicresponse was significantly attenuated versus placebo [26] andreduction of epidermal thickness and lymphocyte infiltrationin human psoriasis [27] both intradermal and topical adminis-tration resulted in a significant decline in thickness of thepsoriatic infiltrate. Revotar recently completed two random-ized double-blind placebo-controlled interventional Phase IIstudies of bimosiamose [28,29]. One study was an ozone-induced sputum neutrophilia model in healthy individualsto support development of inhaled bimosiamose for COPD.The other was to evaluate safety and efficacy of bimosiamosecream used to treat chronic plaque type psoriasis. There wereno results accompanying these reports.Revotar has also described new crystalline forms of bimosia-

mose [30] for pharmaceutical and dermatologic applications.They have expanded use to include cosmetic applicationssuch as skin aging [31] and treatment of IL-8-mediated viralinfections [32]. Efficacy data from porcine and murine modelsof loss of skin elasticity and skin aging from hormone loss orUV damage are reported in the patent literature; however, no

peer reviewed publications were identified. The reduction ofIL-8 by bimosiamose was a surprise clinical trial finding.Patients were treated by inhalation of the disodium salt ofbimosiamose for 10 days. The unit dose strength for nebuliza-tion was 70 mg in 4 ml of 0.9% NaCl twice a day. IL-8 in thesputum supernatant was significantly reduced by treatmentrelative to pretreatment values. The mechanism by which thisis achieved has not been clearly defined by the patent authors.Presumably, it is through inhibition of signaling that upregu-lates inflammatory mediators such as TNF-a and INF-g thatin turn induce IL-8 expression. Additionally, TBC-1269 hasbeen shown to inhibit respiratory syncytial virus, an impor-tant respiratory pathogen in infants and children. Activity wasdemonstrated in vitro and in a mouse model of infection [33].

Revotar, under license from Encysive, is also developing aninjectable formulation of bimosiamose (TBC-1269) for psori-asis and atopic dermatitis. A Phase IIa trial of the subcutane-ous injectable formulation of bimosiamose in patients withpsoriasis has been conducted as a proof-of-concept trial.This pilot study in patients with moderate-to-severe plaquepsoriasis reportedly had promising results [34].

Taisho Pharmaceuticals has filed patent applications relatedto persulfated oligosaccharides as L- and P-selectin inhibi-tors [35]. Their data show that binding between biotinylatedversican (also known as chondroitin sulfate proteoglycancore protein 2) and L- and P-selectins was inhibited to thesame degree by a persulfated chondroitin sulfate/dermatansulfate chain such as chondroitin polysulfate, dermatanpolysulfate and chondroitin sulfate E.

Activatedplatelet

P-selectin

L-selectin

P-selectin

Leukocyte

Blood flow

PSGL-1

TF-richmicroparticles

MitogensE-selectin

Chemokines

Activated endothelium

Macrophage

Sub-endothelialmatrix

Foam cell

Figure 2. Depiction of a blood vessel showing cell-type localization of selectins.



Exp

ert O

pin.

The

r. P

aten

ts D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Sydn

ey o

n 09

/02/

14Fo

r pe

rson

al u

se o

nly.

2.2 Non-carbohydrate small molecule inhibitorsRevotar has also been working on pyrogallol derivativesas selectin inhibitors. This series was designed asnon-glycosylated/non-glycosidic/non-peptidic small moleculePSGL-1 mimetics. Their most potent compound (4.1)is 10-fold more potent than the clinical compound

bimosiamose against E-, P- and L- selectins in the sLex tyro-sine sulfate assay (sLexTSA) [36]. In addition, other trihydroxyphenyl compounds have been described [37] some of which(e.g., (4.2)) show improved potency over (4.1) in the sLexTSAassay. The dimethoxy and dihydroxy phenyl derivativesdisclosed [38] are less potent. Compound (4.3) showed

OCOC6H5HO3S

HO3S

SO3HCO2H

HHN

H

HN

N

N

OO O

O

O

O OO

O

O

OHOH

OHOH

OH

O

O OO

O

OCOC6H5

CO2H

OHOH

OHOH

OH

O

CO2H

(CH2)8

NaO3S

SO3Na

SO3Na

O

O OO

O

O

O

O O

NH

HN

NH

HN

HN

N

N

OO

OH

OH

OH

OHOH

OH

OH

OH

OH

OH

OH

OH

HOAcHN

3.1

3.3

3.2

3.4

OCOC6H5

CO2H OO O

O

H

HN

H

H OOHOH

OHOH

OH

OH

OH

O

O N

N

O

O OO

N

N

HN

N

HO3S

SO3H

Figure 3. Selected compounds in a series of BASA-based compounds and a pseudo-oligosaccharide cyclohexane derivative

described by GlycoMimetics as pan selectin inhibitors.BASA: Benzyl amino sulfonic acid.

Bedard & Kaila


Exp

ert O

pin.

The

r. P

aten

ts D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Sydn

ey o

n 09

/02/

14Fo

r pe

rson

al u

se o

nly.

comparable potency to bimosiamose but was less potent than(4.1) and (4.2) in the sLexTSA assay. A non-acid containingtrimethoxy phenyl analogue (4.4) [39] showed comparableactivity to (4.1). Limited data available from Revotar patentapplications for the nitrocatechol derivatives [40] showanalogues (e.g., (4.5)) to be more potent against P- andL- selectins versus E-selectin in the sLexTSA assay.Researchers at Wyeth (now Pfizer) have filed patent

applications relating to quinoline salicylic acids as P-selectininhibitors [41,42]. Their lead compound, PSI-697 (Figure 5),

has reached Phase I clinical trials. Published data have shownthat PSI-697 inhibits P-selectin-dependent leukocyte rollingin mouse and rat [43,44]. It has also shown efficacy in diseasemodels of atherosclerosis in mouse [45], restenosis in rat [43],and venous thrombosis in rat [46] and baboon [47]. A recentpublication also shows ex vivo activity in humans inhibitingthrombus formation [48]. A second generation series, the a-substituted quinoline salicylic acids, was recently filed on bythe same group for the treatment of inflammatory vasculardisorders [49,50]. This series reportedly has improved aqueous

HO

O

O

OHO

HOOH

OH

(CH2)4 OH

O

O

O

OH

HO

HOOH

OH

HO OH

HN

O

SOH

O

NH

OO

O

O OH

O

TBC1269

4.24.3

HO

O

HN

O OH

OH

OH4.1

NO2HN

O

OH

HO

S

OH

O

4.5

NH

O

NH2

O

O

O

4.4

Figure 4. Bimosiamose 1,6-bis[3-(3-carboxymethylphenyl)-4-(2-a-D-mannopyranosyloxy)phenyl]hexane (TBC1269) and

selected polyphenol derivatives in various stages of development by Revotar.



Exp

ert O

pin.

The

r. P

aten

ts D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Sydn

ey o

n 09

/02/

14Fo

r pe

rson

al u

se o

nly.

solubility and pharmacokinetic profile. Published data showinhibition of thrombus formation in baboon at a lower dosethan PSI-697 [51]. The second generation lead compoundPSI-421 (Figure 5) has reached the predevelopment stage.

Rimonyx pharmaceuticals has filed patent applications relat-ing to sulfonylbenzo-aminothieno [2,3-c]pyridines as L- and P-selectin antagonists, useful in the treatment of inflammatoryand autoimmune diseases [52]. Compound (5.1) has shown effi-cacy in mouse models including TIP, carrageenan-inducedpaw edema and delayed type hypersensitivity models at dosesranging from 2 to 50 mg/kg.

Patent applications relating to several non-glycosidic andnon-peptidic inhibitors of E- and P-selectins have beenpatented by researchers at the University of Mainz JohannesGutenberg. Compound (5.2) has shown efficacy in a mouseperitonitis model [53].

Astellas Pharma (formerly Yamanouchi Pharmaceuticals)has identified polyhydroxy phenols, mainly gallic acid deriva-tives, as potent P-selectin inhibitors. They have attached thesecompounds to peptides or peptide mimetics. In addition, theyhave filed patent applications on glucose-based compounds aspotent P-selectin inhibitors [54-57]. Gallic acid was evaluated ina mouse endothelial cell inflammation model. It showed 50%reduction in leukocyte-platelet conjugates in the femoralvein of aged atherosclerotic ApoE-/- mice when infused at1.5 mg/kg/h.

2.3 Non-carbohydrate high molecular mass molecule

inhibitorsPatent applications on dendritic polyglycerol sulfate andsulfonates have been filed by researchers at Charite Universi-taetsmedizin describing use in inflammatory disease asP- and L-selectin inhibitors. A critical size as well as densityof sulfation of the polymer core is important for activity.Compounds are also useful for imaging diagnostics especiallyfor inflammatory diseases [58].

2.4 Peptides/recombinant protein inhibitorsA patent application was filed by Genetics Institute andTemple University describing amelioration of IRI by block-ade of P-selectin with peptide/protein [59]. Subsequently, Y’sTherapeutics under license from Wyeth is developing YSPSL(rPSGL-Ig) for delayed graft rejection in cadaveric kidneys, toprevent IRI. In a Phase II trial completed in 2008, YSPSL wasshown to significantly improve early graft function in terms ofserum creatinine reduction and increased glomerular filtrationrate, specifically in patients at high risk for renal IRI. YSPSLalso reduced expression of IRI biomarkers [60]. An additionalPhase II in cadaveric liver transplant is reportedly ongoing [61].rPSGL-Ig is efficacious in steatotic rat liver models of ex vivocold ischemia followed by reperfusion or transplantation [62].In the model of cold ischemia/reperfusion, livers pre-treated ex vivo with rPSGL-Ig at harvesting from obeseZucker rats showed significantly decreased portal resistance,increased bile production and diminished hepatic endothelial

neutrophil infiltration, as compared with untreatedcontrols. Pretreatment of fatty livers with rPSGL-Ig prior totransplantation extended the survival of lean Zucker ratrecipients from 40 to 90%.

Novavax, in collaboration with the US National Instituteof Neurological Disorders and Stroke (NINDS), was develop-ing recombinant E-selectin proteins as tolerogens adminis-tered intranasally for the secondary prevention of stroke.Published data provide experimental evidence on preventionof ischemic and hemorrhagic stroke in spontaneously hyper-tensive stroke-prone rats [63]. The company was awarded agovernment contract for the formulation development andmanufacture of E-selectin for Phase I clinical trials to be runby the NINDS and the NIH [64]. However, no recent patentactivities and no development since 2002 have been reported.

2.5 mAb inhibitorsTakeda acquired Cytel Corp. but no further development hasbeen reported of the discontinued cylexin, an sLex pentasac-charide. Instead, Takeda reported Phase I development ofCY-1787 and CY-1747 mAbs against E- and P-selectins,respectively. Development was discontinued in favor ofhumanized versions of the antibodies, CY-1788 and CY-1748 [65]. However, as of this writing, no further developmentof these humanized mAbs has been reported either.

Researchers at Aeres Biomedical described compositionsand methods for treating inflammation and other pathologi-cal conditions using novel blocking P-selectin antibodies [66].They demonstrated the ability to block platelets binding toleukocytes with a humanized anti-P-selectin antibody,PB1.3. The antibody, ABC 48, was in preclinical testing forpotential prevention and treatment of deep vein thrombosis.No further development has been reported since 2003.

Genetics Institute and Temple University’s 2003 patentapplication describing amelioration of IRI by blockade of P-selectin with peptide/protein [59] included specific descriptionof antibodies to P-selectin and to a P-selectin ligand modula-tion of leukocyte--endothelial interactions following ischemiausing a P-selectin antagonist. However, there are no reportsof ongoing research with such antibodies.

Ligocyte researchers have described methods for the treat-ment and prevention of pulmonary infections using one ormore anti-selectin agent [67]. Data presented in the patentapplication appear to have been a serendipitous findingwhen attempting to show that treating an inflammatorycondition by selectin blockade would not inhibit the body’sability to fight infection. In fact, it was demonstrated that a1 mg/kg dose of the mAb EL246 improved clearance ofboth Pseudomonas aeruginosa and non-Pseudomonas bacteriafrom ovine lung. The mAb, EL246 binds to a specific anti-genic determinant on both E- and L-selectins, and inhibitsE- and L-selectin cell adhesion function [68]. Additionally,EL246 dosed 1 mg/kg to non-human primates at (-15)minutes relative to LPS challenge and again at 1 h post LPSchallenge also reduced inflammatory cell recruitment relative

Bedard & Kaila


Exp

ert O

pin.

The

r. P

aten

ts D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Sydn

ey o

n 09

/02/

14Fo

r pe

rson

al u

se o

nly.

to control. Myeloperoxidase was also reduced by ~ 70%.Research suggests that these data show potential for treatmentof acute exacerbations of diseases such as COPD and asthmain which recruitment of neutrophils and macrophages arecommonly seen. EL246 (Eleuquin) is under predevelopmentby LigoCyte for the treatment of acute inflammatory condi-tions such as COPD, ischemic reperfusion injury andtransplant reject.Hoffmann La Roche researchers have described a P-selectin

antibody variant. This invention relates generally to anti-P-selectin antibodies and, in particular, to anti-P-selectin anti-bodies that do not bind complement factor C1q. Preferably,these antibodies are human or humanized antibodies [69].Their data show that the antibodies of the inventionare more potent than non-mutated parent antibodies atinhibiting the adhesion HL60 cells to purified P-selectin

coated onto microtiter plates. The antibodies are also inhibi-tors in a rosetting assay measuring the adhesion ofthrombin-activated platelets to HL60 cells. The antibodiesaccording to the invention bind to P-selectin CHO cellswith EC50 values in the range of 0.01 and 0.07 µg/ml. EC50

values on E-selectin CHO cells and L-selectin 300.19 cellsare preferably above 100 µg/ml. They are functional undershear conditions inhibiting the adhesion of human leukocytesto a platelet monolayer in a concentration-dependent mannerat a shear rate of 65/s. And they block adhesion of leukocytesto human endothelial cells expressing P-selectin. A number ofthe antibodies were evaluated by surface plasmon resonance(Biacore). Kds ranged from 1 � 10-9 to 2 � 10-11 M [69].

Selexys Pharmaceuticals has described chimeric or human-ized antibodies, which recognize P-selectin and which areuseful for the treatment of inflammatory and thrombotic

N

OH Cl

CO2H

N

OH Cl

CO2H

CF3

O

OH

HO

NS

SN

NH

O

S

O

O

N

N

H3CO2C

H3CO2C

H3CO2C

O

O O(CH2)9CH3

O(CH2)9CH3

PSI-697 PSI-421

5.4

5.1

5.2

NH

N

HN N

R

R2

R

5.3

Figure 5. Selected non-carbohydrate small molecules in development by Wyeth (PSI-697 and PSI-421), Rimonyx (5.1), the

University of Mainz Johannes Gutenberg (5.2), Eisai (5.3) and Novogen (5.4).



Exp

ert O

pin.

The

r. P

aten

ts D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Sydn

ey o

n 09

/02/

14Fo

r pe

rson

al u

se o

nly.

conditions such as sickle cell disease, pain associated withsickle cell disease, deep vein thrombosis, asthma, rheumatoidarthritis, psoriasis and IRI. They show Biacore data forhumanized mouse antibody, ‘Glaggr’. The apparent Kd forGlaggr is 31.1 nM, compared to the parental G1 murine anti-body Kd of 24.4 nM. There was no binding observed foreither antibody to E-selectin [70].

2.6 Nucleotide inhibitorsGilead/Nexstar described high-affinity oligonucleotideligands to lectins, specifically nucleic acid ligands having theability to bind to the lectins, wheat germ agglutinin, L-, E-and P-selectins and the methods for obtaining such ligands.Published data show oligonucleotides with equilibrium disso-ciation constants for aptamer/P-selectin binding is reported torange from 16 to 710 pM. In vitro, their aptamers reportedlybind with subnanomolar affinities to P-selectin expressed onthrombin-activated platelets, inhibit the binding of P-selec-tin-IgG chimera to sLex and to neutrophils, and block thebinding-activated platelets to neutrophils in flow cytometryand in hydrodynamic assays [71]. L-selectin specific aptamersare reported to inhibit L-selectin binding to immobilizedsLex in static in vitro assays, inhibit L-selectin-mediated rolling of human lymphocytes and neutrophils onactivated endothelial cells under flow and block L-selectin-dependent lymphocyte trafficking in severe combined immu-nodeficiency mice. Aptamers were selected by SystematicEvolution of Ligands by Exponential Enrichment technology,a process based on oligonucleotide combinatorial chemistryand in vitro selection, to develop specific aptamer antago-nists. Development of both L- and P-selectin aptamers hasreportedly been discontinued [72].

Archemix is developing a P-selectin aptamer for the poten-tial treatment of sickle cell disease [73]. It is not clear whetheror not this is a previously described P-selectin apatamer [74].Preclinical IND-enabling studies are under way in the US.

3. Modulation of selectin activity byinhibition of selectin expression

Another lesser used approach for attenuating selectin-mediatedinflammation is through inhibition of selectin expression.

3.1 Non-carbohydrate small moleculesResearchers at Eisai have patented deazapurines (5.3) for thetreatment of inflammatory or autoimmune and proliferativediseases [75-77]. These compounds inhibit expression ofE-selectin and intercellular adhesion molecule 1 (ICAM-1).They were tested for their ability to inhibit E-selectinexpression in primary HUVECs using ELISA assays.

Novogen researchers have filed patent applications on iso-flavone derivatives as inhibitors of expression of cell adhesionmolecules such as E-selectin. Isoflavones are naturally occur-ring compounds found in soy and textured vegetables. Thecompounds are described for treatment of cardiovascular

and inflammatory diseases [78]. More recently, a review co-authored by one of the inventors discusses the use of isofla-vones in the treatment of pancreaticobiliary cancer and theirmechanisms of action. It describes a potent genisten deriva-tive, phenoxodiol (3-(4-hydroxyphenyl)-2H-1-benzopyran-7-ol) (5.4), which reportedly was well tolerated in a Phase Itrial [79] and inhibits E-selectin expression. However, it alsosaid to inhibit vascular cell adhesion molecule 1 (VCAM-1)expression, IL-8 and TNF-a secretion, and induces apoptosisthrough multiple signaling mechanisms. So, it is not a specificE-selectin inhibitor.

3.2 NucleotidesIn addition to using nucleotides to directly block ligandreceptor interaction, they are also being used to inhibit selec-tin synthesis. Eberhard Karls University has described the useof a nucleic-acid molecule, a genetic construct and siRNAmolecules to inhibit of the expression of endothelial adhesionmolecules, specifically, E-selectin, ICAM and VCAM [80].Such treatment could be used in vessel grafting, lung trans-plantation, treatment of lung transplants and a method oftreatment of the open heart within the scope of cardioplegia.Endothelial cells were isolated from sections of the venasaphena magna, obtained from coronary artery bypass graft-ing patients. Cultured cells were transfected with specificsiRNA and nonspecific siRNA controls and then stimulatedwith TNF-a. Specifically, transfected cells showed significantinhibition of the expression of the respective adhesion mole-cules, as measured by flow cytometry analysis. In the case ofE-selectin (CD-62E), the level of expression was significantlyreduced [81].

Antisense Pharma Gmbh has described the use of oligonu-cleotides or antisense oligonucleotides in inhibiting thesynthesis of proteins involved in the formation of metastases,including selectins [82]. The majority of published datapertains to TGF-b2 inhibitor, AP 12009, in clinical develop-ment against malignant tumors [83]. There were no obviousdata supporting the described ability to inhibit of selectins.

4. Modulation of selectin activity by ligandcleavage

Genetics Institute Researchers described invention of compo-sitions of purified native or recombinantly expressed mocar-hagin protein and its potential use in inflammatory diseasesincluding a variety of thrombotic disorders such as restenosisand DVT. Mocarhagin is a metalloproteinase-disintegrinfamily protein found in the cobra venom and has beenfound to cleave a 10 amino-acid peptide from the mature Nterminus of PSGL-1, resulting in disruption of P- and L-selectin-mediated cell adhesion [84-86]. A cDNA encoding amocarhagin protein (‘clone NMM-1’) has also been clonedfrom a cobra venom gland library. The nucleotide sequencewas deposited with the American Type Culture Collection(ATCC 209588). Applicants have also discovered that

Bedard & Kaila


Exp

ert O

pin.

The

r. P

aten

ts D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Sydn

ey o

n 09

/02/

14Fo

r pe

rson

al u

se o

nly.

removal of the mocarhagin propeptide increases the catalyticactivity of the enzyme. Mocarhagin proteolytic activity isdefined as the ability to digest PSGL-1, such as in a PSGL-1digestion assay and/or inhibiting the binding of P-selectin toneutrophils or HL60 cells. There are no reports offurther development.

5. Conclusion

Since 2003, half as many patent applications were fileddescribing novel means of inhibiting selectins as were reportedin our previous review [9]. However, positive data in humanshave now been reported in psoriasis, kidney transplant,asthma and COPD. The majority of these data have beenclinical trials with compounds covered under previouslyreported patent literature, such as bimosiamose and YPSL. Anumber of other selectin inhibitors have made it into theclinic, but failed to demonstrate efficacy. Inhibition strategiesdescribed include direct inhibition of receptor/ligand bindingusing carbohydrate molecules, carbohydrate mimetics, non-carbohydrate small and high molecular mass molecules, pepti-des, antibodies and aptamers (nucleotides). Ligand cleavageand inhibition of selectin synthesis have also been described.

6. Expert opinion

The absolute number of patents/patent applications filed inthe field of selectin inhibition has diminished in recent years;however, the innovation and sophistication of inhibitors hasincreased significantly. The field of selectin antagonism holdsunique challenges, especially for small molecule inhibitors.Inhibiting protein--protein interactions that occur underflow presents technical barriers. Natural ligands bind with rel-atively low affinity to a shallow binding surface rather thanspecific well-defined pocket. Static assays often require signalamplification leading to increased variability in results thatmay not be predictive of in vivo behavior. However, recentyears have brought increasingly sophisticated flow assayswith definable shear force. Surface plasmon resonance is wellsuited to measuring both low affinity protein--protein interac-tions and inhibition of those interactions. Parallel flow cham-bers, and superior analysis software, allow quantification ofcell--cell, cell--protein or protein-coated sphere--proteininteractions. Intravital microscopy (IVM) takes this samereal time quantification in vivo. These advances have madestructure--activity relationships much more attainable andinhibitor optimization more productive.The next most important breakthrough in the field

has been linking selectin inhibition in vitro and in in vivomechanistic models (IVM) to in vivo efficacy in disease

models. Typically, micromolar inhibitors would not be con-sidered drug-like. However, data now show that inhibitionconcentrations decrease from static cell-based assays, to pro-tein/protein assays, to cell/cell assays under flow. And thatmicromolar inhibition in vitro can translate to in vivo efficacyin the complex system in which selectins function.

Other breakthroughs include new classes of inhibitors suchas aptamers for which current technology now allows relativeease of synthesis and identification of these structurally stableand low immunogenic molecules [87]. New disease indicationssuch as sickle cell anemia and seizures for selectin antagonismmay offer the potential advantage of orphan drug status thatwould facilitate clinical development.

The real driving force moving forward will be additionalpositive clinical data. The small molecule, bimosiamose, isthe most advanced selectin antagonist in this respect. It wouldappear that pan selectin antagonism is a factor in this demon-strated efficacy but remains to be seen if this is a requirementand/or depends on disease indication. Bimosiamose hasdemonstrated positive Phase II data, in both safety and effi-cacy, in obstructive airways disease (decreased the late asth-matic response to allergen challenge), respiratory tractdisorders (reduced lymphocyte count and IL-8 in sputum inCOPD patients) and skin disorders (improvement in psoria-sis). The recombinant protein, YPSL, has also demonstratedsafety and efficacy in human trials. YPSL has improved earlygraft function in terms of serum creatinine reduction andincreased glomerular filtration rate, specifically in patients athigh risk for renal IRI. YSPSL also reduced expression ofIRI biomarkers [60]. A Phase II in cadaveric liver transplantis reportedly ongoing. These data validate the predictivityof existing in vitro and in vivo models. Additional positiveclinical data in studies with larger enrollment are needed toconfirm these results. But even these early data should serveto further our understanding in existing methodologies andencourage exploration of new inhibitor technologies andnew indications.

Acknowledgements

The authors thank M Eberle, Senior Information Scientist, atPfizer, formerly Wyeth Research, for performing the patentand pipeline database searches necessary for this article; andcolleagues R Camphausen and GD Shaw for use of originalfigures adapted for Figures 1 and 2.

Declaration of interest

The authors are employees of Pfizer, formerly WyethResearch.



Exp

ert O

pin.

The

r. P

aten

ts D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Sydn

ey o

n 09

/02/

14Fo

r pe

rson

al u

se o

nly.

Bibliography

1. Wagner DD, Frenette PS. The vessel wall

and its interactions. Blood

2008;111(11):5271-81

2. Kaila N, Somers WS, Thomas BE, et al.

Quinic acid derivatives as sialyl

Lewis(x)-mimicking selectin inhibitors:

design, synthesis, and crystal structure in

complex with E-selectin. J Med Chem

2005;48(13):4346-57

3. Somers WS, Tang J, Shaw GD,

Camphausen RT. Insights into the

molecular basis of leukocyte tethering

and rolling revealed by structures of P-

and E-selectin bound to sLex and

PSGL-1. Cell 2000;103(3):467-79

4. Leppanen A, Yago T, Otto VI, et al.

Model glycosulfopeptides from P-selectin

glycoprotein ligand-1 require tyrosine

sulfation and a core 2-branched O-glycan

to bind to l-selectin. J Biol Chem

2003;278(29):26391-400

5. Frennette PS, Wagner DD. Insights into

selectin function from knockout mice.

Thromb Haemost 1997;78(1):60-4

6. Ludwig RJ, Sch€on MP, Boehncke W-H.

P-selectin. Expert Opin Ther Targets

2007;11(8):1103-17

7. Rossi B, Constantin G. Anti-selectin

therapy for the treatment of

inflammatory diseases. Inflamm Allergy

Drug Targets 2008;7(2):85-93

8. Boehncke W-H, Sch€on MP. Interfering

with leukocyte rolling -- a promising

therapeutic approach in inflammatory

skin disorders? Trends Pharmacol Sci

2003;24(2):49-52

9. Kaila N, Thomas BE. Selectin inhibitors.

Expert Opin Ther Patents

2003;13(3):305-17

10. Regents of the University of California.

Heparin compositions and selectin

inhibition. WO2007014049; 2007

11. Stevenson JL, Varki A, Borsig L. Heparin

attenuates metastasis mainly due to

inhibition of P- and L-selectin, but

non-anticoagulant heparins can have

additional effects. Thromb Res

2007;120(Suppl 2):S107-S11

12. Hostettler N, Naggi A, Torri G, et al.

P-selectin- and heparanase-dependent

antimetastatic activity of

non-anticoagulant heparins. FASEB J

2007;21(13):3562-72

13. Ludwig RJ. Therapeutic use of heparin

beyond anticoagulation. Cur Drug

Discov Technol 2009;6:281-9

14. Min W, Yanguang G, Meihong T, et al.

Selectively desulfated heparin inhibits

P-selectin-mediated adhesion of human

melanoma cells. Cancer Lett

2005;229(1):123-6

15. Adis R&D Insight Database. PGX 100.

Wolters Kluwer Health; 2009

16. ParinGenix. A study designed to evaluate

ODSH in subjects with exacerbations of

COPD. National Institutes of Health;

2009

17. GlycoMimetics, Inc. Glycomimetic

antagonists for both E-and P-selectins.

WO2005054264; 2005

18. GlycoMimetics, Inc. Specific antagonist

for both E-and P-selectins.

WO2005051920; 2005

19. GlychoTech, Inc. Compounds and

methods for inhibiting selectin-mediated

function. WO2003097658; 2003

20. GlycoMimetics, Inc. Heterobifunctional

pan-selectin inhibitors.

WO2007028050; 2007

21. GlycoMimetics, Inc. Glycomimetic

replacements for hexoses and N-acetyl

hexosamines. US20080161546; 2008

22. GlycoMimetics, Inc. Methods of use of

glycomimetics with replacements for

hexoses and N-acetyl hexosamines.

US20080200406; 2008

23. ClinicalTrials.gov. Study of intravenous

GMI-1070 in adults with sickle cell

disease. NIH; 2009

24. Chang J, Patton J, Sarkar A, et al.

A novel selectin antagonist, GMI-1070,

prevents vaso-occlusion in sickle cell mice

by inhibiting leukocyte adhesion and

activation. 49th Annual Meeting;

American Society of Hematology. Blood

2007;110(11):2245

25. Texas Biotechnology Corp. Di-and

trivalent small molecule selectin

inhibitors. WO1997001335; 1999

26. Beeh K, Beier J, Meyer M, et al.

Bimosiamose, an inhaled small-molecule

pan-selectin antagonist, attenuates late

asthmatic reactions following allergen

challenge in mild asthmatics:

a randomized, double-blind,

placebo-controlled clinical

cross-over-trial. Pulm Pharmacol Ther

2006;19(4):233-41

27. Friedrich M, Bock D, Philipp S, et al.

Pan-selectin antagonism improves

psoriasis manifestation in mice and man.

Arch Dermatol Res 2006;297(8):345-51

28. ClinicalTrials.gov. Safety and efficacy

study of bimosiamose cream to treat

psoriasis. NIH; 2009

29. ClinicalTrials.gov. Study to evaluate the

effect of bimosiamose on ozone induced

sputum neutrophilia. NIH; 2009

30. Revotar Biopharmaceuticals AG.

Crystalline forms of 1,6-bis [3-(3-

carboxymethylphenyl)-4-(2-alpha-d-

mannopyranosyl-oxy)-phenyl] hexane.

WO2008028966; 2008

31. Revotar Biopharmaceuticals AG. Use of

1,6-bis [3-(3-carboxymethylphenyl)-4-(2-

alpha-d-mannopyranosyl-oxy)-phenyl]

hexane for the preparation of cosmetic

compositions. WO2008028950; 2008


Pharmaceutical composition for the

treatment of IL-8 mediated diseases.

WO2008098985; 2008

33. Malhotra R, Ward M, Bright H, et al.

Isolation and characterisation of potential

respiratory syncytial virus receptor(s) on

epithelial cells. Microbes Infect

2003;5(2):123-33

34. Insight. ARD. Bimosiamose; 2009

35. Taisho Pharma Co., Ltd. Persulfated

oligosaccharide acting on selectins and

chemokine. WO2004011662; 2006

36. Revotar Biopharmaceuticals AG. Novel

phloroglucinol derivatives having selectin

ligand activity. WO2007039112; 2007


Non-glycosylated/non-glycosidic/

non-peptidic small molecule PSGL-1

mimetics for the treatment of

inflammatory disorders.

WO2005090284; 2005


multi-cyclic compounds.

WO2007039111; 2007


aromatic compounds and their use in

medical applications.

WO2007039113; 2007


nitrocatechol derivatives having selectin

ligand activity. WO2007039114; 2007

Bedard & Kaila


Exp

ert O

pin.

The

r. P

aten

ts D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Sydn

ey o

n 09

/02/

14Fo

r pe

rson

al u

se o

nly.

41. Wyeth Corp. Methods and

compositions for selectin inhibition.

WO2005047258; 2005



WO2005047257; 2005

43. Bedard PW, Clerin V, Sushkova N,

et al. Characterization of the novel

P-selectin inhibitor PSI-697

[2-(4-chlorobenzyl)-3-hydroxy-7,8,9,10-

tetrahydrobenzo[h]

quinoline-4-carboxylic acid] in vitro

and in rodent models of vascular

inflammation and thrombosis.

J Pharmacol Exp Ther

2008;324(2):497-506

44. Kaila N, Janz K, Huang A, et al.

2-(4-chlorobenzyl)-3-hydroxy-7,8,9,10-

tetrahydrobenzo[h]quinoline-4-carboxylic

acid (PSI-697): identification of a clinical

candidate from the quinoline salicylic

acid series of P-selectin antagonists.

J Med Chem 2006;50(1):40-64

45. Clerin V, Resmini C, Wong T, et al.

WAY-197697, a P-selectin antagonist,

reduces atherosclerosis in apolipoprotein

E deficient mice. Intern Soc Thromb

Haemost Meeting. J Thromb Haemost

2005;3(Suppl 1):abstract P2355

46. Myers DD Jr, Henke PK, Bedard PW,

et al. Treatment with an oral small

molecule inhibitor of P-selectin

(PSI-697) decreases vein wall injury in a

rat stenosis model of venous thrombosis.

J Vasc Surg 2006;44(3):625-32

47. Myers DD Jr, Wrobleski S, Longo C,

et al. Resolution of venous thrombosis

using a novel oral small-molecule

inhibitor of P-selectin (PSI-697) without

anticoagulation. J Thromb Haemost

2007;97(3):400-7

48. Chelliah R, Lucking AJ, Tattersall L,

et al. P-selectin antagonism reduces

thrombus formation in humans.

J Thromb Haemost 2009;11:1915-9



WO2008121805; 2008

50. Wyeth Corp. Methods and compositions

for selectin inhibition and quinoline

derivatives and pharmaceutical

compositions comprising them

for selectin inhibition.

WO2008121817; 2008

51. Meier T, Myers DD Jr, Wrobleski S,

et al. Prophylactic P-selectin inhibition

with PSI-421 promotes resolution of

venous thrombosis without

anticoagulation. J Thromb Haemost

2008;99(2):343-51

52. Rimonyx Pharmaceuticals Ltd.

Pharmaceutical compositions comprising

thieno[2,3-c]pyridine derivatives and use

thereof. WO2004069149; 2008

53. University of Mainz Johannes Gutenberg.

Non-glycosidic and non-peptidic selectin

inhibitors, and the use thereof.

WO2006010598; 2006

54. Astellas Pharma, Inc (Yamanouchi

Pharma). P-selectin targeting ligand and

compositions there of

WO2004105783; 2007

55. Astellas Pharma, Inc (Yamanouchi

Pharma Co LTD). Polyhydroxy phenols

and their use in binding P-selectin.

WO2004105740; 2007

56. Astellas Pharma Europ BV. Compounds

binding to P-selectin.

WO2004018502; 2009

57. Astellas Pharma Europ BV (Yamanouchi

Europ BV). Glucose-based

compounds with affinity to

P-selectin. WO2004033473; 2007

58. Freie Uni Berlin; Charite

Universitaetsmedizin. Dendritic

polyglycerol sulfates and sulfonates and

their use for inflammatory diseases.

WO2008015015; 2008

59. Genetics Institute LLC; Temple

University. Modulation of

leukocyte-endothelial interactions

following ischemia.

US20030083258; 2003

60. Gaber AO, Moore LW, Mulgaonkar S,

et al. YSPSL (rPSGL-Ig) for the

prevention of delayed graft function

(DGF): Results of double-blind,

placebo-controlled, multi-center

phase I/II safety and efficacy study: 832.

Transplantation 2008;86(2):290

61. ClinicalTrials.gov. YSPSL for prevention

of ischemic reperfusion injury in patients

undergoing cadaveric orthotopic liver

transplantation. NIH; 2009

62. Amersi F, Farmer DG, Shaw GD, et al.

P-selectin glycoprotein ligand-1 (rPSGL-

Ig)-mediated blockade of CD62 selectin

molecules protects rat steatotic liver grafts

from ischemia/reperfusion injury.

Am J Transplant 2002;2(7):600-8

63. Chen Y, Ruetzler C, Pandipati S, et al.

Mucosal tolerance to E-selectin provides

cell-mediated protection against ischemic

brain injury. Proc Natl Acad Sci USA

2003;100(25):15107-12

64. Reuters. Novavax inc (nvax.O) company

profile. 2009. Available from: http://www.

reuters.com/finance/stocks/companyProfile?

rpc=66&symbol=NVAX.O.

[Cited 28 October 2009]

65. PJB Pharmaprojects PRDPI. CY-1787.

Informa; 2009

66. Aeres Biomedical Ltd. Antibodies to

P-selectin and their uses.

EP642356; 2003

67. Ligocyte Pharmaceuticals, Inc.; Univ

Montana. Methods for the treatment and

prevention of infection using anti-selectin

agents. WO2006083322; 2006

68. Jutila M, Watts G, Walcheck B,

Kansas G. Characterization of a

functionally important and evolutionarily

well-conserved epitope mapped to the

short consensus repeats of E-selectin and

L-selectin. J Exp Med

1992;175(6):1565-73

69. Hoffmann La Roche, Inc. Anti-P-selectin

antibodies. US20050226876; 2005

70. Selexys Pharmaceuticals Corp.

Anti-P-selectin antibodies and methods

of using the same to treat inflammatory

diseases. WO2008069999; 2008

71. Jenison R, Jennings S, Walker D, et al.

Oligonucleotide inhibitors of

P-selectin-dependent neutrophil-platelet

adhesion. Antisense Nucleic Acid

Drug Dev 1998;8(4):265-79

72. IMS R&D Focus. Aptamers targeted to

P-selectin and to L-selectin for the

treatment of inflammatory disorders,.

IMS Health Global Services; 2003

73. IMS R&D Focus. Aptamer P-selectin

inhibitor for the potential treatment of

sickle cell disease. IMS Health Global

Services; 2008

74. Archemix Corp. Nucleic acid ligand to

B. anthracis protective antigen.

WO2004085665; 2004

75. Eisai Co., Ltd. Deazapurines and uses

thereof. US7314936; 2008

76. Eisai Co., Ltd. Novel deazapurines and

uses thereof. WO2004063336; 2004

77. Eisai Co., Ltd. Deazapurines and uses

thereof. WO2003057696; 2003

78. Novogen Research PTY LTD. Treatment

of restenosis. US20050119301; 2005

79. Saif MW, Tytler E, Lansigan F, et al.

Flavonoids, phenoxodiol, and a novel

agent, triphendiol, for the treatment of



Exp

ert O

pin.

The

r. P

aten

ts D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Sydn

ey o

n 09

/02/

14Fo

r pe

rson

al u

se o

nly.

pancreaticobiliary cancers. Exp Opin

Investig Drugs 2009;18(4):469-79

80. Eberhard Karls University. Sirna

molecules for the treatment of blood

vessels. WO2006077112; 2008

81. Walker T, Wendel HP, Tetzloff L, et al.

Inhibition of adhesion molecule

expression on human venous endothelial

cells by non-viral siRNA transfection.

J Cell Mol Med 2007;11(1):139-47

82. Antisense Pharma GmbH.

Pharmaceutical composition.

WO2005084712; 2005

83. Schlingensiepen K, Fischer-Blass B,

Schmaus S, Ludwig S. Antisense

therapeutics for tumor treatment: The

TGF-beta2 inhibitor AP 12009 in

clinical development against malignant

tumors. Recent Results Cancer Res

2008;177:137-50

84. Gardiner EE, De Luca M, McNally T,

et al. Regulation of P-selectin binding to

the neutrophil P-selectin counter-receptor

P-selectin glycoprotein ligand-1 by

neutrophil elastase and cathepsin G.

Blood 2001;98(5):1440-7

85. Ward CM, Vinogradov DV,

Andrews RK, Berndt MC.

Characterization of mocarhagin, a cobra

venom metalloproteinase from Naja

mocambique mocambique, and related

proteins from other Elapidae venoms.

Toxicon 1996;34(10):1203-6

86. Genetics Institute. Highly purified

mocarhagin cobra venom protease

polynucleotides endcoding same and

related proteases and therapeutic uses

thereof. US6413760; 2002

87. Barbas A, White R. The development

and testing of aptamers for cancer.

Cur Opin Investig Drugs

2009;10(6):572-8

AffiliationPatricia W Bedard†1 BS & Neelu Kaila§2 PhD†,§Authors for correspondence1Pfizer, BioTherapeutics,

Biocorrections Research Unit,

200 CambridgePark Drive,

Cambridge, MA 02140, USA

Tel: +1 617 665 5336; Fax: +1 617 665 5386;

E-mail: [email protected], PharmaTherapeutics,

Worldwide Chemistry,

200 CambridgePark Drive,

Cambridge, MA 02140, USA

Bedard & Kaila


Exp

ert O

pin.

The

r. P

aten

ts D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Sydn

ey o

n 09

/02/

14Fo

r pe

rson

al u

se o

nly.

selectin inhibitors: a patent review

Documents