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.
Christian Harcken  1 ,  Doris Riether  1 ,  Pingrong Liu  1 ,  Hossein Razavi  1 ,  Usha Patel  1 ,  Thomas Lee  1 ,  Todd Bosanac  1 ,  Yancey Ward  1 ,  Mark Ralph  1 ,  Zhidong Chen  1 ,  Donald Souza  1 ,  Richard M Nelson  1 ,  Alison Kukulka  1 ,  Tazmeen N Fadra-Khan  1 ,  Ljiljana Zuvela-Jelaska  1 ,  Mita Patel  1 ,  David S Thomson  1 ,  Gerald H Nabozny  1
Affiliations
  • 1. Department of Medicinal Chemistry and Department of Immunology and Inflammation, Boehringer Ingelheim Pharmaceuticals, Inc. , 900 Ridgebury Road, Ridgefield, Connecticut 06877, United States.
PMID: 25516791 DOI: 10.1021/ml500387y
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.
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