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Publication Abstract from PubMed

The retinoic acid receptor-related orphan nuclear receptor gammat (RORgammat), a promising therapeutic target, is a major transcription factor of genes related to psoriasis pathogenesis such as interleukin (IL)-17A, IL-22, and IL-23R. On the basis of the X-ray cocrystal structure of RORgammat with 1a, an analogue of the known piperazine RORgammat inverse agonist 1, triazolopyridine derivatives of 1 were designed and synthesized, and analogue 3a was found to be a potent RORgammat inverse agonist. Structure-activity relationship studies on 3a, focusing on the treatment of its metabolically unstable cyclopentyl ring and the central piperazine core, led to a novel analogue, namely, 6-methyl-N-(7-methyl-8-(((2S,4S)-2-methyl-1-(4,4,4-trifluoro-3-(trifluoromethyl)b utanoyl)piperidin-4-yl)oxy)[1,2,4]triazolo[1,5-a]pyridin-6-yl)nicotinamide (5a), which exhibited strong RORgammat inhibitory activity and a favorable pharmacokinetic profile. Moreover, the in vitro and in vivo evaluation of 5a in a human whole-blood assay and a mouse IL-18/23-induced cytokine expression model revealed its robust and dose-dependent inhibitory effect on IL-17A production.

Discovery of [1,2,4]Triazolo[1,5-a]pyridine Derivatives as Potent and Orally Bioavailable RORgammat Inverse Agonists.,Nakajima R, Oono H, Sugiyama S, Matsueda Y, Ida T, Kakuda S, Hirata J, Baba A, Makino A, Matsuyama R, White RD, Wurz RRho, Shin Y, Min X, Guzman-Perez A, Wang Z, Symons A, Singh SK, Mothe SR, Belyakov S, Chakrabarti A, Shuto S ACS Med Chem Lett. 2020 Feb 27;11(4):528-534. doi:, 10.1021/acsmedchemlett.9b00649. eCollection 2020 Apr 9. PMID:32292560^[1]

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