ABSTRACT
In the search of a potential backup for clopidogrel, we have initiated a HTS campaign designed to identify novel reversible P2Y12 antagonists. Starting from a hit with low micromolar binding activity, we report here the main steps of the optimization process leading to the identification of the preclinical candidate SAR216471. It is a potent, highly selective, and reversible P2Y12 receptor antagonist and by far the most potent inhibitor of ADP-induced platelet aggregation among the P2Y12 antagonists described in the literature. SAR216471 displays potent in vivo antiplatelet and antithrombotic activities and has the potential to differentiate from other antiplatelet agents.
Subject(s)
Indoles/pharmacology , Platelet Aggregation Inhibitors/pharmacology , Platelet Aggregation/drug effects , Purinergic P2 Receptor Antagonists/pharmacology , Pyridazines/pharmacology , Receptors, Purinergic P2Y12/metabolism , Acute Coronary Syndrome/prevention & control , Adenosine Diphosphate/pharmacology , Administration, Oral , Animals , Binding, Competitive , CHO Cells , Cricetinae , Cricetulus , Humans , Indoles/chemical synthesis , Indoles/metabolism , Injections, Intravenous , Male , Models, Chemical , Molecular Structure , Platelet Aggregation Inhibitors/chemical synthesis , Platelet Aggregation Inhibitors/metabolism , Purinergic P2 Receptor Antagonists/chemical synthesis , Purinergic P2 Receptor Antagonists/metabolism , Pyridazines/chemical synthesis , Pyridazines/metabolism , Rats , Rats, Sprague-Dawley , Receptors, Purinergic P2Y12/genetics , Thrombosis/prevention & controlABSTRACT
Compound 15 (SAR107375), a novel potent dual thrombin and factor Xa inhibitor resulted from a rational optimization process. Starting from compound 14, with low factor Xa and modest anti-thrombin inhibitory activities (IC50's of 3.5 and 0.39 µM, respectively), both activities were considerably improved, notably through the incorporation of a neutral chlorothiophene P1 fragment and tuning of P2 and P3-P4 fragments. Final optimization of metabolic stability with microsomes led to the identification of 15, which displays strong activity in vitro vs factor Xa and thrombin (with Ki's of 1 and 8 nM, respectively). In addition 15 presents good selectivity versus related serine proteases (roughly 300-fold), including trypsin (1000-fold), and is very active (0.39 µM) in the thrombin generation time (TGT) coagulation assay in human platelet rich plasma (PRP). Potent in vivo activity in a rat model of venous thrombosis following iv and, more importantly, po administration was also observed (ED50 of 0.07 and 2.8 mg/kg, respectively). Bleeding liability was reduced in the rat wire coil model, more relevant to arterial thrombosis, with 15 (blood loss increase of 2-fold relative to the ED80 value) compared to rivaroxaban 2 and dabigatran etexilate 1a.
