Structure-Based Design of Macrocyclic Coagulation Factor VIIa Inhibitors
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- 作者：E. Scott Priestley ; Daniel L. Cheney ; Indawati DeLucca ; Anzhi Wei ; Joseph M. Luettgen ; Alan R. Rendina ; Pancras C. Wong ; Ruth R. Wexler
- 刊名：Journal of Medicinal Chemistry
- 出版年：2015
- 出版时间：August 13, 2015
- 年：2015
- 卷：58
- 期：15
- 页码：6225-6236
- 全文大小：539K
- ISSN：1520-4804
文摘
On the basis of a crystal structure of a phenylpyrrolidine lead and subsequent molecular modeling results, we designed and synthesized a novel series of macrocyclic FVIIa inhibitors. The optimal 16-membered macrocycle was 60-fold more potent than an acyclic analog. Further potency optimization by incorporation of P1鈥?alkyl sulfone and P2 methyl groups provided a macrocycle with TF/FVIIa Ki = 1.6 nM, excellent selectivity against a panel of seven serine proteases, and FVII-deficient prothrombin time EC2x = 1.2 渭M. Discovery of this potent, selective macrocyclic scaffold opens new possibilities for the development of orally bioavailable FVIIa inhibitors.