Blockade of protease-activated receptor-4 (PAR4) provides robust antithrombotic activity with low bleeding.

Antiplatelet agents are proven efficacious treatments for cardiovascular and cerebrovascular diseases. However, the existing drugs are compromised by unwanted and sometimes life-threatening bleeding that limits drug usage or dosage. There is a substantial unmet medical need for an antiplatelet drug with strong efficacy and low bleeding risk. Thrombin is a potent platelet agonist that directly induces platelet activation via the G protein (heterotrimeric guanine nucleotide-binding protein)-coupled protease-activated receptors PAR1 and PAR4. A PAR1 antagonist is approved for clinical use, but its use is limited by a substantial bleeding risk. Conversely, the potential of PAR4 as an antiplatelet target has not been well characterized. Using anti-PAR4 antibodies, we demonstrated a low bleeding risk and an effective antithrombotic profile with PAR4 inhibition in guinea pigs. Subsequently, high-throughput screening and an extensive medicinal chemistry effort resulted in the discovery of BMS-986120, an orally active, selective, and reversible PAR4 antagonist. In a cynomolgus monkey arterial thrombosis model, BMS-986120 demonstrated potent and highly efficacious antithrombotic activity. BMS-986120 also exhibited a low bleeding liability and a markedly wider therapeutic window compared to the standard antiplatelet agent clopidogrel tested in the same nonhuman primate model. These preclinical findings define the biological role of PAR4 in mediating platelet aggregation. In addition, they indicate that targeting PAR4 is an attractive antiplatelet strategy with the potential to treat patients at a high risk of atherothrombosis with superior safety compared with the current standard of care.

Prediction of the therapeutic index of marketed anti-coagulants and anti-platelet agents by guinea pig models of thrombosis and hemostasis.

INTRODUCTION: Animal models of thrombosis and hemostasis are critical for target validation in pharmaceutical research. Guinea pig haemostatic mechanisms, such as the platelet thrombin receptor repertoire, resemble those of humans. Measuring the performance characteristics of marketed antithrombotic drugs in guinea pig models is a key to predicting therapeutic indices of new agents. The goal of the current study was to benchmark representative marketed drugs in thrombosis and hemostasis models in guinea pigs. METHODS: Effects of the cyclooxygenase inhibitor, aspirin, the P2Y(12) antagonist, clopidogrel, the glycoprotein IIb/IIIa inhibitor, tirofiban, and the direct thrombin inhibitors, argatroban and hirudin, were evaluated in this study. Antithrombotic agents were tested in FeCl(3)-induced carotid artery thrombosis and arterio-venous shunt thrombosis models. Haemostatic effects of drugs were evaluated in cuticle and renal bleeding models. Ex vivo measurements of platelet function and coagulation inhibition were performed to benchmark preclinical doses of each agent to those used clinically. RESULTS: The overall rank-order of potency in thrombosis models based on per cent of vessels occluded, average carotid blood flow, and thrombus weight was aspirin=argatroban=tirofiban

(3R,5S,E)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(methyl(1-methyl-1h-1,2,4-triazol-5-yl)amino)pyrimidin-5-yl)-3,5-dihydroxyhept-6-enoic acid (BMS-644950): a rationally designed orally efficacious 3-hydroxy-3-methylglutaryl coenzyme-a reductase inhibitor with reduced myotoxicity potential.

3-hydroxy-3-methylglutaryl coenzyme-A reductase (HMGR) inhibitors, more commonly known as statins, represent the gold standard in treating hypercholesterolemia. Although statins are regarded as generally safe, they are known to cause myopathy and, in rare cases, rhabdomyolysis. Statin-dependent effects on plasma lipids are mediated through the inhibition of HMGR in the hepatocyte, whereas evidence suggests that myotoxicity is due to inhibition of HMGR within the myocyte. Thus, an inhibitor with increased selectivity for hepatocytes could potentially result in an improved therapeutic window. Implementation of a strategy that focused on in vitro potency, compound polarity, cell selectivity, and oral absorption, followed by extensive efficacy and safety modeling in guinea pig and rat, resulted in the identification of compound 1b (BMS-644950). Using this discovery pathway, we compared 1b to other marketed statins to demonstrate its outstanding efficacy and safety profile. With the potential to generate an excellent therapeutic window, 1b was advanced into clinical development.

Novel dual action AT1 and ETA receptor antagonists reduce blood pressure in experimental hypertension.

Angiotensin II and endothelin-1 activate their respective AT(1) and ET(A) receptors on vascular smooth muscle cells, producing vasoconstriction, and both peptides are implicated in the pathogenesis of essential hypertension. Angiotensin II potentiates the production of endothelin, and conversely endothelin augments the synthesis of angiotensin II. Both AT(1) and ET(A) receptor antagonists lower blood pressure in hypertensive patients; thus, a combination AT(1)/ET(A) receptor antagonist may have greater efficacy and broader utility compared with each drug alone. By rational drug design a biphenyl ET(A) receptor blocker was modified to acquire AT(1) receptor antagonism. These compounds (C and D) decreased Sar-Ile-Angiotensin II binding to AT(1) receptors and endothelin-1 binding to ET(A) receptors, and compound C inhibited angiotensin II- and endothelin-1-mediated Ca(2+) transients. In rats compounds C and D reduced blood pressure elevations caused by intravenous infusion of angiotensin II or big endothelin-1. Compound C decreased blood pressure in Na(+)-depleted spontaneously hypertensive rats and in rats with mineralocorticoid hypertension. Compound D was more efficacious than AT(1) receptor antagonists at reducing blood pressure in spontaneously hypertensive rats, and its superiority was likely due to its partial blockade of ET(A) receptors. Therefore compounds C and D are novel agents for treating a broad spectrum of patients with essential hypertension and other cardiovascular diseases.