Optimization of drug-like properties of nonsteroidal glucocorticoid mimetics and identification of a clinical candidate

Christian Harcken; Doris Riether; Pingrong Liu; Hossein Razavi; Usha Patel; Thomas Lee; Todd Bosanac; Yancey Ward; Mark Ralph; Zhidong Chen; Donald Souza; Richard M Nelson; Alison Kukulka; Tazmeen N Fadra-Khan; Ljiljana Zuvela-Jelaska; Mita Patel; David S Thomson; Gerald H Nabozny

doi:10.1021/ml500387y

Optimization of drug-like properties of nonsteroidal glucocorticoid mimetics and identification of a clinical candidate

ACS Med Chem Lett. 2014 Nov 20;5(12):1318-23. doi: 10.1021/ml500387y. eCollection 2014 Dec 11.

Authors

Christian Harcken¹, Doris Riether¹, Pingrong Liu¹, Hossein Razavi¹, Usha Patel¹, Thomas Lee¹, Todd Bosanac¹, Yancey Ward¹, Mark Ralph¹, Zhidong Chen¹, Donald Souza¹, Richard M Nelson¹, Alison Kukulka¹, Tazmeen N Fadra-Khan¹, Ljiljana Zuvela-Jelaska¹, Mita Patel¹, David S Thomson¹, Gerald H Nabozny¹

Affiliation

¹ Department of Medicinal Chemistry and Department of Immunology and Inflammation, Boehringer Ingelheim Pharmaceuticals, Inc. , 900 Ridgebury Road, Ridgefield, Connecticut 06877, United States.

Abstract

A series of nonsteroidal "dissociated" glucocorticoid receptor agonists was optimized for drug-like properties such as cytochrome P450 inhibition, metabolic stability, aqueous solubility, and hERG ion channel inhibition. This effort culminated in the identification of the clinical candidate compound ( R )-39.

Keywords: Glucocorticoid mimetics; anti-inflammatory agents; azaindoles; drug-like properties; glucocorticoid-induced osteoporosis; nonsteroidal glucocorticoids.