Lead Compound S007-867 (Anti-platelet)
  • Unique Features of the Molecule:

    Unique collagen mediated platelet activation Inhibitor

  • Inhibits collagen induced platelet activation

  • Novel mechanism of action as a specific inhibitor of collagen induced platelet aggregation and adhesion

  • Executive Summary
  • CDRI has a novel small molecule anti-platelet compound which may be useful in treating intravascular arterial thrombosis. This novel compound (chiral) is patented and has unique scaffold. The compound was picked after extensive SAR studies, which are active and selectively inhibit collagen mediated platelet activation. The compound is relatively simple to synthesize (MW < 500) and can easily be chemically modified to obtain the desired ratio of anti-platelet activity. The anti-platelet molecule has shown definite activity in animal models of arterial thrombosis. Preclinical studies show the compound to have lower incidences of bleeding as compared to currently used agents such as aspirin and clopidogrel. Acute toxicity studies in rats and mice studies demonstrate a favourable safety profile of this compound.

  • Economic Burden and Market
  • Cardiovascular disease (CVD) is a major cause of death and disability and of rising health care cost around the world. According to World Health Organization (WHO) estimates, in 2005, 17.5 million people died of CVD and 15 million suffered stroke. This is 30 percent of all deaths globally. Around 80% of CVD deaths took place in low and middle-income countries. India accounts for 60% of global burden – 118 million in 2000, 214 million in 2025 (projected) with CVD becoming the leading cause of death in developing countries. CVD is known to claim about 1 in every 2.5 deaths in the United States. Coronary artery disease (CAD), whose pathogenesis is often attributed to atherosclerosis of the pericardial vessels, has been found to be responsible for 48% of deaths from CVD.
  • Arterial thrombosis remains one of the most significant causes of coronary artery disease. Although there are several marketed therapies, they are often associated with unwanted side effects. The vastness of the clinical problem clearly indicates that targeted therapies would find niche markets.
  • Antithrombotic drugs are used in the management of clinical conditions like deep vein thrombosis (DVT), pulmonary embolism (PE), peripheral artery disease (PAD), and acute coronary syndromes (ACS). Antithrombotic drugs are one of the most rapidly growing sectors of the cardiovascular market representing >$20 billion USD in sales.

  • Unmet Therapeutic Need
  • Currently available antithrombotic drugs are associated with significant drawbacks that limit their use. Hence there is a real unmet clinical need for developing novel and safer antithrombotic agents. An increasing number of people are presenting with risk factors for thromboembolic events due to the rapidly aging population.
  • Background and Opportunity
  • The most common cause of death in the developed world is acute myocardial infarction, which is caused by coronary artery thrombosis. Platelets have a central role in cardiovascular thrombosis. They adhere to the sub-endothelial matrix after endothelial damage due to a ruptured atherosclerotic plaque, and then aggregate with each other to form a pro-thrombotic surface that promotes clot formation and subsequently vascular occlusion. As a result, therapies targeting key pathways of platelet activation including thromboxane A2 synthesis, ADP-mediated signalling and integrin αIIbβ3 (also known as GPIIb–IIIa) signalling has established a role in the treatment of cardiovascular arterial.
  • The most common of these anti-platelet agents include aspirin, clopidogrel and integrin αIIbβ3 antagonists. Limitations of current therapies include weak inhibition of platelet function (for example, by aspirin), blockade of only one pathway of ADP mediated signalling (for example, by clopidogrel), slow onset of action (for example, of clopidogrel), inter-patient response variability with poor inhibition of platelet response in some patients (for example, to clopidogrel), the inability to transform the success of intravenous integrin αIIbβ3 antagonist therapy into oral therapy and the inability to completely separate a reduction in thrombotic events from an increase in bleeding events.
  • Over the last decade, considerable progress has been made in identifying and describing the molecular events regulating the initiation of thrombus formation. The platelet–collagen interaction has received the most attention because collagen is abundant in atherosclerotic plaques, where it contributes to lesion growth and arterial narrowing. Collagen receptors may be better targets because their over expression is associated with stroke and myocardial infarction, whereas their absence produces only a modest prolongation in bleeding time. GPVI-depleted mice displayed significantly reduced brain infarct volumes at day 1 after transient middle cerebral artery occlusion model. This was further confirmed by studies showing that elevated GPVI expression levels in platelets are associated with an increased risk of stroke occurrence in humans, and elevated levels of the soluble GPVI ecto-domain have been detected in acute ischemic stroke suggesting increased GPVI activation in this setting. Strategies for inhibiting the collagen–platelet interaction include humanized monoclonal antibodies and aptamers against the receptors, small-molecule peptide inhibitors, and proteins derived from the leech. Few of these agents have been tested in humans, and are still under various phases of clinical trials.
  • Highlights
  •  Pharmacological inhibition of collagen activation is considered to be protective and lesion specific target. Compound S007-867 is a potent and specific inhibitor of collagen induced platelet activation.
  • It is a specific inhibitor of collagen induced platelet activation.

  • It has no effect on coagulation cascade proteins (TT, PT aPTT) and has no adverse effect on vasoreactivity.

  • It is orally active, as evident by sustained efficacy in mice model of thrombosis.

  • It has mild effect on bleeding time with better efficacy, in contrast to existing anti-platelet drugs Aspirin and Clopidogrel at the similar efficacy doses administered by oral route.

  • It significantly prolonged time of occlusion in FeCl3 induced arterial thrombosis in rat, mice and hamsters, and reduced thrombus weight in arterio-venous shunt model in rat and hamsters
  • Preclinical safety pharmacological, mutagenic and limited toxicity studies conducted so far have demonstrated no adverse effect. It has been tested in vitro for binding to 451 kinases and important GPCRs, which predict its safety.

  • Good pharmacokinetic properties and bioavailability.

  • Advantages of CDRI Compound

  • Clinicians have used combination anti-thrombotic drug therapies to improve the antithrombotic efficacy. The combined use of antiplatelet agents, however, is considered high-risk by many clinical centers due to increased bleeding tendencies. In addition identification of resistance of these drugs is also a matter of great concern. Potent antiplatelet action selectively against collagen mediated platelet activation offers a novel approach to resolve the bleeding problem. The key advantage of the new compound is related to a novel mechanism of action: Collagen antagonism. Unlike the known anti-platelet drugs, it does not enhance the bleeding time to a very high level as observed with clinically used anti-platelet drugs, thus it is expected to reduce bleeding risks.

  • Patent Status 
      Patent filed:   Chiral 3-aminomethylpiperidine derivatives as inhibitors of collagen induced platelet activation and adhesion
      Indian Application No.   208DEL2011, Dt. 25-Jan-12
      Europe Application No.   12705463.3, Dt. 23-Jul-13
     United states Application No.,   13/995336, Dt. 18-Jun-13
      PCT Application No   PCT/IN2011/000032, Dt. 12-Jan-12