Orally bioavailable pyridine and pyrimidine-based Factor XIa inhibitors: Discovery of the methyl N-phenyl carbamate P2 prime group

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• 作者：James R. Corte<sup> ; sup><sup>james.corte@bms.com" class="auth_mail" title="E-mail the corresponding authorsup> ; Tianan Fang ; Donald J.P. Pinto ; Michael J. Orwat ; Alan R. Rendina ; Joseph M. Luettgen ; Karen A. Rossi ; Anzhi Wei ; Vidhyashankar Ramamurthy ; Joseph E. Myers Jr. ; Steven Sheriff ; Rangaraj Narayanan ; Timothy W. Harper ; Joanna J. Zheng ; Yi-Xin Li ; Dietmar A. Seiffert ; Ruth R. Wexler ; Mimi L. Quan
• 关键词：Factor XIa ; FXIa ; Thrombosis ; Activated partial thromboplastin time ; aPTT
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：15 May 2016
• 年：2016
• 卷：24
• 期：10
• 页码：2257-2272
• 全文大小：4599 K

文摘

Pyridine-based Factor XIa (FXIa) inhibitor (S)-<strong class="boldFont">2strong> was optimized by modifying the P2 prime, P1, and scaffold regions. This work resulted in the discovery of the methyl N-phenyl carbamate P2 prime group which maintained FXIa activity, reduced the number of H-bond donors, and improved the physicochemical properties compared to the amino indazole P2 prime moiety. Compound (S)<strong class="boldFont">-17strong> was identified as a potent and selective FXIa inhibitor that was orally bioavailable. Replacement of the basic cyclohexyl methyl amine P1 in (S)-<strong class="boldFont">17strong> with the neutral p-chlorophenyltetrazole P1 resulted in the discovery of (S)<strong class="boldFont">-24strong> which showed a significant improvement in oral bioavailability compared to the previously reported imidazole (S)-<strong class="boldFont">23strong>. Additional improvements in FXIa binding affinity, while maintaining oral bioavailability, was achieved by replacing the pyridine scaffold with either a regioisomeric pyridine or pyrimidine ring system.