Pharmaceutical chemistry

Hit to lead

Chemistry in R&D

Exploratorydevelopment

Fulldevelopment

IDEA

Drug

CANDIDATE POCTARGET

Therapeuticresearch

Exploratoryresearch

Synthesis optimization

hit/lead identification

Optimization of the leadsTo improve potency, selectivity, PK or reduce toxicity

Hit to lead

• Hit/lead identification

• Leads’ optimization

• Synthesis otpimization

• Chemoinformatics

• Combinatorial chemistry

Medicinal chemistry

Organic chemistry

Chemistry in R&DHit to lead

Research operating plan

Human and rat functional assay

Rat liver slice enzyme inductionCYP450 inhibition

hERG, hPXR

Further characterization in other models

Rapid rat PK

h- and rP2Y12 EC50 <100 nMh- and rP2Y12 Emax > 80%

selectivity over P2Y2,4,etc > 100

Platelet aggregation test

AUC > 1000 nM.hr

Hit to lead

Compounds generetedby medicinal chemistry

P2Y12 antagonists SAR

Hit to lead

ADP

From ADP to AZD6140

Drug Discovery Process

Massimiliano Beltramo, PhD

The patent• To assure the intellectual property to the inventor. • To forbid to competitors the production, use and

commercialization of the invention for 20 years.

What could be claimed ?New moleculesPharmaceutical formulationSynthesis processes and industrial processes Therapeutic indicationDiagnostics’ methodsBiological tools (gene, transfected cell lines, assays, etc)

When to patent a molecule?•In lead optimisation. This normally allow 10 years of exclusivity on the market

What are the characteristics of a candidate?

Biological propertiesBiological properties• Pharmacological profile

(potency, selectivity, efficacy in vivo)

• Pharmacokinetic profile(Biodisponibility, long lasting effect)

• Preliminary toxicological profile (tolerability, hERG, mechanism based toxicity, acute

therapeutic window)

Chemo-physical propertiesChemo-physical properties• Scalability• Pharmaceutical formulation

Commercial potentialCommercial potential• Unmet medical need• Differentiation

• BID acceptable with incremental efficacy

• No titration

• Oral QD

• Titration ~2-4 weeks (GB)Dosing

• Superior• Dizziness, somelence (GB),

nausea, vomiting (Dulox)Tolerability

• Similar• Minimal safety issuesSafety

• Greater responder rate ( >50%)

• 30 % -50% responders Efficacy

• All Neuropathic Pains • Some types of Neuropathic pain

– (DbN, chemotherapy, HIV)Indication

Candidate

differentiatorGold Standards’

Profile

Neuropathic pain. Gold Standards: Gabapentin/Pregabalin/Duloxetine

Candidate Profile

Small Medium High

PERCEIVED DIFFERENTIATION

Hig

h M

ediu

m L

ow

UN

ME

T N

EE

D

Indication Efficacy

Safety Dosing

Tolerability

ottimale

accettabile

nonaccettabile

R&D process for a new drug

Exploratorydevelopment

Fulldevelopment

IDEA

DRUG

CANDIDATE POCTARGET

Therapeuticresearch

Exploratoryresearch

Candidate development

Candidate development objectives

1. To complete the study on the candidate and to establish

• Safety in human

• Suitability for industrial development (exploratory development)

2. To establish the efficacy profile in human and to define the commercial value of the new drug (full development)

R&D process for a new drug

Exploratorydevelopment

Fulldevelopment

DRUG

CANDIDATE POC

Phase IVPost marketing

Surveillance

Phase I (A and B)

Safety

Phase II Study in the

patient

Phase III Study in the

patient

Therapeutic efficacy

Registration

Pre-marketing

Phase 0 orPreclinical development

Developpability

Phase 0 Phase 0 Preclinical developmentPreclinical development

• ADME

• Preclinical Safety e Toxicology

• Chemistry development

• Formulation

Is the molecule suitable to be developped in a drug?

ADMEADME-Absorption-Distribution-Metabolism-Excretion Elimination

Describes the disposition of a pharmaceutical compound within an organism.

Drug exposure to the tissues influence the performance and pharmacological activity of the compound.

Administration route

Intravascular

• Directly into the blood streem

• Immediate and full absorption

It is the preferred route when an immediate effect

is necessary

Intravenous Intra-arterial

Extravascular

• Absorption is retarded and incomplete

All the other cases

Oral

Sublingual

Buccal

Intramuscular

Subcutaneous

Dermal

Bioavailability• Fraction of administered dose that reaches the

systemic circulation in the unchanged form and the target tissue

• After intravenous administration, the drug is completely bioavailable (F=1)

• For oral administration, incomplete bioavailability may be due to:– Transporter Effects– Incomplete absorption or loss in the feces– First pass metabolism in the gut lumen and/or liver

• Major determinant for the differences in dose between the intravascular and extravascular routes

M

Tissues(Site of Action)

Heart

D

D

VenaCava

M

SystemicCirculation

Kidney

Cp

Time

D•Clearance•Distribution•Elimination

M

•Excretion of parent•Excretion of metabolite

M

D

Bile Duct •Metabolism•Biliary Excretion•CYP Inhibition•CYP Induction•Transporters

Liver

D

M

D

M

Legend

D = Parent DrugM = Metabolite(s)

•Re-absorption of drug•Hydrolysis of glucuronide&reabsorption of parent

SmallIntestine

•Dissolution•Acid Instability•Digestive Enzymes•Permeability•Intestinal oxidation or conjugation•p-Glycoprotein efflux•GI Transit time•Bacterial metabolism

GI Tract

D

D

OrallyAdministered

Drug (D)

D

Portal Vein

The fate of a drug

Plasma concentration

0

10

20

30

40

50

60

70

0 2 4 6 8 10

Time (hours)

i.v. route

oral route

Bioavailability: (AUC)oral / (AUC)iv

Bioavailability using different route is

calculated using equal doses

Bioavailability

Understanding Dose-Related Exposure(single-rising dose: SRD)

Dose

AUCor

Cmax

Case A:Linear (i.e dose-proportional PK)

Absorption & Clearance are constant

Dose

AUCor

Cmax

Case B:

Saturable Elimination

Dose

AUCor

Cmax

Case C:

Saturable Absorption

The Ideal DMPK Profileversus Lead Optimization

High oral bioavailability:Half-life between 12 and 24 hr:Multiple elimination pathways:

No reactive metabolites:No human-specific metabolites:

No inhibition of CYP450 enzymes:No induction of CYP enzymes:

Low inter-subject variability/ cost of goodsQD dosing/ acceptable accumulationDrug-drug interactions (DDI) less likelyAvoid safety issues/ idiosyncratic AEsSimplifies safety program & risk assessmentDrug unlikely to cause DDIsAvoid autoinduction or DDIs

RationaleClinical DMPK Profile

Drug Safety DMPK Profile

Good PK with developable form:Acceptable exposure multiples:

Stable and predictable exposure:Clean in AMES test:

Crystalline form - reduced bioavailability?Human risk assessmentReliably target appropriate exposureAvoid mutagens