RESEARCH & DEVELOPMENT

New approaches to developing antithrombotic drugs

-Martin Gallagher-

With cardiovascular disease still the leading cause of death in the US and Europe (it accounts for about 50% of mortality in the US), the search for new and more effective cardiovascular treatments remains a top priority in phannaceutical research. It is therefore of no surprise that the complex area of cardiovascular disease in general, and thrombosis in particular, was one of the main themes of the 13th International Symposium on Medicinal Chemistry [Paris, France; September 1994]. Several presentations at the conference focused on the approaches currently being used to identify antithrombotic 112ents with therapeutic potential.

In recent years there has been 'an explosion . .. in biological information describing the specific enzymes and biological processes involved in the coagulation process', said Dr Bill Ripka of Corvas International.

Dr Ripka outlined the methods currently employed at Corvas to develop synthetic inhibitors of the enzymes involved in coagulation. This process begins with the development of so-called 'pharmacophore maps', and involves the use of algorithms and a certain amount of insight.

The general outline of the coagulation process is relatively well known [see figure 1]. What remains to be determined is the precise structure of the enzymes and receptors involved, and the best sites for inter­vention. All of this information has important implications for novel drug design.

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Figure 1: The coagulation process

At present, it is known that a zymogen and a co­factor are required for the generation of functional coagulation enzymes, and that these must be trans­formed into active enzymes.

This process offers several points for intervention. The transformation to active enzymes can be suppressed by inhibiting the converting enzyme, by blocking or destroying the protein cofactor, or by preventing surface assembly. However, the general feeling is that it is better to intervene at the earliest stage possible, as amplification of the enzymes occurs during the coagulation cascade.

ThrgeUing factor Xa A key enzyme in the coagulation cascade is

the serine protease Factor Xa, a 59kD protein that catalyses the conversion of prothrombin to thrombin.

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Factor Xa inhibitors in development

Drug Manufacturer Phaaeof development

Danaparoid sodium Akzo Launched

CY-222 Sanofi III

Decmatan sulfate Opocrin III

SR·90107 Sanofi II

Aprosulfate sodium Sankyo , CordednAS Corvas Preclinical compounds

DX-9065A Daiichl Preclinical

GL-522 Genelabs PredlnicaJ

Factor Xa inhibitors Mochlda Selectlde Preclinical

The starting point in the development of synthetic inhibitors of Factor Xa at Corvas involved looking at naturally occurring inhibitors. These include: • human tissue factor pathway inhibitor • ecotin (isolated from Escherichia coli) • tick anticoagulant protein (TAP) • antistatin.

TAP, in particular, is a potent and selective inhibItor of ractor Xa. Researchers at Corvas have determined the 3-dimensional structure of this 60 amino acid peptide and are currently developing injectable and oral formulations of synthetic Factor Xa inhibitors based on this knowledge. These are referred to as cordecin AS compounds.

Daiichi investigates Factor Xa too Dr Nagahara from Daiichi also presented details of

the development of Factor Xa inhibitors. Researchers at Daiichi have synthesised a number of 3-(amidino­aryl)-2-4-[(3S)-3-pyrrolidinyloxy]phenyl] propanoic acid derivatives that are low molecular weight, orally active, non peptide Factor Xa inhibitors.

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The most promising compound, DX-9065A, is a potent (IC5o = 0.07IlM) and selective Factor Xa inhibitor. In preclinical studies, it doubled plasma recalcification time (PRCT) at 0.51lM and signific­antly prolonged activated partial thromboplastin time (APTT) at an oral dose of 100 mg/kg, but had no activity against thrombin. This antithrombotic effect was demonstrated in an arterial-venous shunt thrombosis model. Other factor Xa inhibitors under development are shown in the table.

INPHARMA- 15 Oct 1 ...

11

12 RESEARCH & DEVELOPMENT

ew approaches to developing antithrombotic drug - continued

Fournier deftIoping tbioxyIosIde derivatiws Dr FD Bellamy of Laboratoires Fournier described

Fournier's investigations of a family of xyloside derivatives that have good antithrombotic activity after oral administration in animal models. Several hundred derivatives were synthesised and underwent pharmacological evaluation.

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An early lead compound was naroparcil [LF-0900551. This compound is currently in early phase II clinical trials as a potential treatment for deep vein thrombosis. Other xyloside derivatives under investigation include eliparcil [LF-0402121, currently in phase I trials, and nefiparcil [LF-0500301, which is still undergoing preclinical evaluation.

Roche deftIoping thrombin Inhibhors The search for low molecular weight thrombin

inhibitors was described by Dr K Hilpert from Hoffman-La Roche. This search began with the discovery of the thrombin selectivity of I-amino­piperidine.

An exhaustive screening of small basic compounds then led to the identification of RO-466240. This compound is a specific, reversible and competitive inhibitor of thrombin (KI in the subnanomolar range). R0-466240 has been selected for clinical invest­igation and phase I trials have been completed. Phase II trials are set to begin shortly in Switzerland.

RO-466240 has a half-life in humans of around 15 minutes after IV administration (oral bioavailability

is poor) and is expected to be used in the emergency room treatment of thrombosis.

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Other agads under dewJopment Servier is evaluating 2 new tripeptide boronic acid

thrombin inhibitors, S-17436 and S-18326. These compounds were derived from DUP-7I4 (Ac-D-Phe­Pro-boroArg) and are currently at the preclinical stage as possible oral antithrombotic agents.

Bristol-Myers Squibb is conducting preclinical studies of BMY-4462 1 , a compound that has been found to double clotting time after oral administration.

SmithKline Beecham has developed SB-20865 1 , a nonpeptide glycoprotein IIBnIlA antagonist with potent antiaggregatory activity after either IV or intradermal administration, with an apparent oral bioavaHability of around 10%.

FPL-67085, a compound under development by Fisons, is a potent and selective antithrombotic agent with a novel mechanism of action. It is a P21£eceptor antagonist and is currently in clinical development as a short-acting infusable antithrombotic agent.

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