Development of Structurally Simplified, Non-azadecalin Glucocorticoid Antagonists which Demonstrate In Vivo Activity

  • J Med Chem. 2026 Apr 23;69(8):9104-9124. doi: 10.1021/acs.jmedchem.5c03567.
Lorna A Duffy  1 ,  Mark T Mills  1 ,  Andrew W Phillips  1 ,  Ian R Strutt  1 ,  Thomas W Hornsby  1 ,  Morgan Jouanneau  1 ,  Bohdan Waszkowycz  1 ,  Sally L Lee  1 ,  Adam P Peall  1 ,  Utsav Bali  1 ,  Iain A S Walters  1 ,  Hazel J Hunt  2
Affiliations
  • 1. Sygnature Discovery, BioCity, Pennyfoot Street, Nottingham NG1 1GF, U.K.
  • 2. Corcept Therapeutics, 101 Redwood Shores Parkway, Redwood City, California 94065, United States.
PMID: 41945481 DOI: 10.1021/acs.jmedchem.5c03567
Abstract

Glucocorticoid Receptor antagonists (GR antagonists) are a class of compounds developed to inhibit the activation of the Glucocorticoid Receptor and they have been used to treat a range of conditions such as Cushing's syndrome, diabetes, glaucoma, and depression. We report herein the discovery and optimization of a series of selective piperazine-based GR antagonists and discuss how key learnings from the discovery of relacorilant (CORT125134) were utilized to identify a simplified scaffold. Several compounds were identified with the desired profile and 3 key compounds were progressed to in vivo proof of concept studies.

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