Papillon, Julien, Adams, Christopher, Hu, Qi-Ying, Singh, Alok, Zhang, Chun, Amaral, Adam, Beil, Michael, Fu, Fumin, Hu, Chii-Whei, Lasala, Daniel, Liang, Guiqing and Rigel, Dean (2015) Structure-Activity Relationships, Pharmacokinetics and In Vivo Activity of CYP11B2 and CYP11B1 Inhibitors. Journal of Medicinal Chemistry, 58 (11). pp. 4749-4770. ISSN 0022-26231520-4804

Abstract

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 which 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’s disease patients. We now report novel series of aldosterone synthase inhibitors with single-digit nanomolar cellular potency and excellent physico-chemical properties. Structure-activity relationships and optimization of their oral bioavailability are presented. An illustration of the impact of the age of pre-clinical models on pharmacokinetic properties is also highlighted. Similar biochemical potency was generally observed against for CYP11B2 and CYP11B1, although emerging structure-selectivity relationships were noted leading to more CYP11B1-selective analogs.

Item Type:	Article
Date Deposited:	12 Aug 2016 00:45
Last Modified:	12 Aug 2016 00:45
URI:	https://oak.novartis.com/id/eprint/25051