Optimization of P2Y₁₂ Antagonist Ethyl 6-(4-((Benzylsulfonyl)carbamoyl)piperidin-1-yl)-5-cyano-2-methylnicotinate (AZD1283) Led to the Discovery of an Oral Antiplatelet Agent with Improved Druglike Properties

Abstract

P2Y12 antagonists are widely used as antiplatelet agents for the prevention and treatment of arterial thrombosis. Based on the scaffold of a known P2Y12 antagonist AZD1283, a series of novel bicyclic pyridine derivatives were designed and synthesized. The cyclization of the ester substituent on the pyridine ring to the ortho-methyl group led to lactone analogues of AZD1283 that showed significantly enhanced metabolic stability in subsequent structure–pharmacokinetic relationship studies. The metabolic stability was further enhanced by adding a 4-methyl substituent to the piperidinyl moiety. Compound 58l displayed potent inhibition of platelet aggregation in vitro as well as antithrombotic efficacy in a rat ferric chloride model. Moreover, 58l showed a safety profile that was superior to what was observed for clopidogrel in a rat tail-bleeding model. These results support the further evaluation of compound 58l as a promising drug candidate.

Synthesis and biological evaluation of N4‐hydrazone derivatives of 5,7‐dihydro‐6H‐pyrrolo[2,3‐d]pyrimidin‐6‐one as novel anticancer agents with antimetastatic adjunct efficacy

“…The aggregation inhibition rate was calculated as follows: inhibition rate (%) = [(control tube maximal aggregation response − test tube maximum aggregation response)/ control tube maximum aggregation response] × 100%. [39,40]…”

Novel Antiplatelet Agents in Cardiovascular Disease

“…100 Also, SAR216471 and AZD1283 are reversible, nonthienopyridine inhibitors of P2Y 12 , which provided good antithrombotic efficacy with a superior safety profile compared to the current P2Y 12 inhibitors in preclinical models (Table 1 and Figure 1). 101,102 Platelet 12-Lipoxygenase 12-Lipoxygenase (12-LOX) uses arachidonic acid to form bioactive metabolites that have been linked with regulation of PAR-4-and GPVI-mediated signaling pathways and FcgRIIa-mediated thrombosis. 103,104 ML355 is the first 12-LOX inhibitor and demonstrated dose-dependent inhibition of human platelet aggregation in vitro (Table 1 and Figure 1).…”

Improved Practical Synthesis of DY‐038, an Oral Available Antiplatelet Agent

“…Moreover, it showed a safety profile that was superior to what was observed for clopidogrel in a rat tail-bleeding model. [12] As the molecule was gearing up to progress into development, we required a safe and robust process that could deliver significant quantities of the drug substance to fund the early clinical needs of this program. Herein, we report the process development efforts to synthesize gram quantities of 1 that represented a significant improvement over the medicinal chemistry route.…”