RESEARCH & DEVELOPMENT

-Robert Short-

There are high expectations regarding the use of phosphodiesterase (PDE) IV inhibitors to treat asthma, as indicated by the many pharmaceutical companies that are investing in the development of these agents [see table]. Recently, efforts have been focused on designing PDE IV inhibitors that are better tolerated than the first-generation agents, but that have at least equivalent therapeutic activity. Progress in this field of research was discussed at an me conference on 'Therapeutic Opportunities for Allergic Diseases' [London, UK; December 1996].

'The greatest challenge in asthma drug develop-ment is to identify drugs that will control asthmatic inflammation as effectively as [cortico-]steroids without side effects, and preferably in an oral preparation', said Professor Peter Barnes from the National Heart and Lung Institute, London, UK.

It is thought that the POE IV inhibitors now under development may have potential in this respect. POE IV inhibitors have been shown to exert potent anti-inflammatory and anti-asthmatic effects both in vitro and in vivo. They exert their anti-inflammatory effect by blocking the activity of POE IV, an enzyme that is found in inflammatory cells.

Hampered by advel'Se effects The clinical use of first-generation POE IV

inhibitors has been hampered by adverse effects, such as nausea, vomiting and gastric acid secretion, said Or Mary Barnette from SmithKline Beecham, US. Accordingly, the current goal of research is to identify 'selective PDE N inhibitors that maintain the anti-asthmatic actions of the first-generation [agents], while decreasing their potential to elicit these side effects' , said Or Barnette ..

Several inter-related strategies now exist to address this issue. One of the key approaches is the investigation of the relative effects of inhibiting 2 SUbtypes of POE IV, which are known as LPOE IV and HPOE IV. The goal is to identify which of these

1173-832419711073-000111$01.00° Adls International Limited 1997. All rights reserved

SUbtypes plays an important role in inflammatory cell function, rather than in parietal cell function or in the central nervous system (CNS).

Getting the balance right Early studies have confirmed that the relative

proportions of LPOE IV and HPOE IV vary among cell types. LPOE IV predominates in inflammatory cells, while HPOE IV predominates in cells found in the CNS and gastric glands.

Consequently, it is possible that certain pharma-cological actions of POE IV inhibitors result from the inhibition of LPOE IV, while others arise from the inhibition of HPOE IV. Along these lines, it is conceivable that beneficial therapeutic effects could be separated from adverse effects by designing compounds that selectively inhibit one SUbtype of POE IV.

'It appears that inhibition of LPDE IV, but not HPDE Iv, is associated with the inhibition of mono-cyte activation,' whereas inhibition of HPDE N is correlated with . .. enhancement of histamine-stimulated acid secretion and emesis [in animal models)" said Or Barnette. A number of in vivo studies have provided evidence of an association between beneficial therapeutic effects and LPOE IV inhibition, and adverse effects and HPOEIV inhibition. Accordingly, increasing the selectivity of compounds for LPOE IV may improve their therapeutic index.

SB-207499 favours LPDE IV Or Barnette used the second-generation POE IV

inhibitor SB-207499 [SmithKline Beecham] to illustrate this. The agent is as active as the fIrst-generation inhibitor rolipram [Schering AG] in terms of inhibiting LPOE IV, but is 10-20 times less active than rolipram with respect to HPOE IV inhibition.

In accordance with this, animal studies have shown that SB-207499 retains activity similar to that of rolipram in terms of inhibiting tumour necrosis factor production in monocytes, but is much less effective in terms of increasing histamine-induced gastric acid secretion. Thus, reducing the affinity for HPOE IV

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12 RESEARCH & DEVELOPMENT

appears to result in an improved experimental therapeutic index.

However, the picture is not completely straight-forward, as not all of the beneficial effects of PDE IV inhibition are associated with the inhibition of LPDE IV activity, said Dr Barnette.

Effects such as the suppressiori of neutrophil degranulation and inhibition of histamine-induced bronchoconstriction are closely associated with the inhibition of HPDE IV, and not LPDE IV. These points will need to be taken into account in future research into PDE IV inhibitor design.

Inphanna- 8 Feb 1997 No. 1073 1173-8324197/1073-000121$01.00° Adls International Limited 1997. All rights reserved