Lead Optimization of Ethyl 6-Aminonicotinate Acyl Sulfonamides as Antagonists of the P2Y12 Receptor. Separation of the Antithrombotic Effect and Bleeding for Candidate Drug AZD1283

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• 作者：Peter Bach ; Thomas Antonsson ; Ruth Bylund ; Jan-Arne Bj枚rkman ; Krister 脰sterlund ; Fabrizio Giordanetto ; J. J. J. van Giezen ; S酶ren M. Andersen ; Helen Zachrisson ; Fredrik Zetterberg
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：September 12, 2013
• 年：2013
• 卷：56
• 期：17
• 页码：7015-7024
• 全文大小：404K
• 年卷期：v.56,no.17(September 12, 2013)
• ISSN：1520-4804

文摘

Synthesis and structure鈥揳ctivity relationships of ethyl 6-aminonicotinate acyl sulfonamides, which are potent antagonists of the P2Y₁₂ receptor, are presented. Shifting from 5-chlorothienyl to benzyl sulfonamides significantly increased the potency in the residual platelet count assay. Evaluation of PK parameters in vivo in dog for six compounds showed a 10-fold higher clearance for the azetidines than for the matched-pair piperidines. In a modified Folts model in dog, both piperidine 3 and azetidine 13 dose-dependently induced increases in blood flow and inhibition of ADP-induced platelet aggregation with antithrombotic ED₅₀ values of 3.0 and 10 渭g/kg/min, respectively. The doses that induced a larger than 3-fold increase in bleeding time were 33 and 100 渭g/kg/min for 3 and 13, respectively. Thus, the therapeutic index (TI) was 鈮?0 for both compounds. On the basis of these data, compound 3 was progressed into human clinical trials as candidate drug AZD1283.