6u25

Publication Abstract from PubMed

RORgammat is an important nuclear receptor that regulates the production of several pro-inflammatory cytokines such as IL-17 and IL-22. As a result, RORgammat has been identified as a potential target for the treatment of various immunological disorders such as psoriasis, psoriatic arthritis, and inflammatory bowel diseases. Structure and computer-assisted drug design led to the identification of a novel series of tricyclic RORgammat inverse agonists with significantly improved in vitro activity in the reporter (Gal4) and human whole blood assays compared to our previous chemotype. Through careful structure activity relationship, several potent and selective RORgammat inverse agonists have been identified. Pharmacokinetic studies allowed the identification of the lead molecule 32 with a low peak-to-trough ratio. This molecule showed excellent activity in an IL-2/IL-23-induced mouse pharmacodynamic study and demonstrated biologic-like efficacy in an IL-23-induced preclinical model of psoriasis.

Rationally Designed, Conformationally Constrained Inverse Agonists of RORgammat-Identification of a Potent, Selective Series with Biologic-Like in Vivo Efficacy.,Marcoux D, Duan JJ, Shi Q, Cherney RJ, Srivastava AS, Cornelius L, Batt DG, Liu Q, Beaudoin-Bertrand M, Weigelt CA, Khandelwal P, Vishwakrishnan S, Selvakumar K, Karmakar A, Gupta AK, Basha M, Ramlingam S, Manjunath N, Vanteru S, Karmakar S, Maddala N, Vetrichelvan M, Gupta A, Rampulla RA, Mathur A, Yip S, Li P, Wu DR, Khan J, Ruzanov M, Sack JS, Wang J, Yarde M, Cvijic ME, Li S, Shuster DJ, Borowski V, Xie JH, McIntyre KW, Obermeier MT, Fura A, Stefanski K, Cornelius G, Hynes J Jr, Tino JA, Macor JE, Salter-Cid L, Denton R, Zhao Q, Carter PH, Dhar TGM J Med Chem. 2019 Oct 31. doi: 10.1021/acs.jmedchem.9b01369. PMID:31638797^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.