Structure鈥揂ctivity Relationships, Pharmacokinetics, and in Vivo Activity of CYP11B2 and CYP11B1 Inhibitors
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- 作者：Julien P. N. Papillon ; Christopher M. Adams ; Qi-Ying Hu ; Changgang Lou ; Alok K. Singh ; Chun Zhang ; Jose Carvalho ; Srinivan Rajan ; Adam Amaral ; Michael E. Beil ; Fumin Fu ; Eric Gangl ; Chii-Whei Hu ; Arco Y. Jeng ; Daniel LaSala ; Guiqing Liang ; Michael Logman ; Wieslawa M. Maniara ; Dean F. Rigel ; Sherri A. Smith ; Gary M. Ksander
- 刊名：Journal of Medicinal Chemistry
- 出版年：2015
- 出版时间：June 11, 2015
- 年：2015
- 卷：58
- 期：11
- 页码：4749-4770
- 全文大小：757K
- ISSN：1520-4804
文摘
CYP11B2, the aldosterone synthase, and CYP11B1, the cortisol synthase, are two highly homologous enzymes implicated in a range of cardiovascular and metabolic diseases. We have previously reported the discovery of LCI699, a dual CYP11B2 and CYP11B1 inhibitor that has provided clinical validation for the lowering of plasma aldosterone as a viable approach to modulate blood pressure in humans, as well normalization of urinary cortisol in Cushing鈥檚 disease patients. We now report novel series of aldosterone synthase inhibitors with single-digit nanomolar cellular potency and excellent physicochemical properties. Structure鈥揳ctivity relationships and optimization of their oral bioavailability are presented. An illustration of the impact of the age of preclinical models on pharmacokinetic properties is also highlighted. Similar biochemical potency was generally observed against CYP11B2 and CYP11B1, although emerging structure鈥搒electivity relationships were noted leading to more CYP11B1-selective analogs.