Discovery of [1,2,4]Triazolo[1,5- a]pyridine Derivatives as Potent and Orally Bioavailable RORγt Inverse Agonists

Ryota Nakajima; Hiroyuki Oono; Sakae Sugiyama; Yohei Matsueda; Tomohide Ida; Shinji Kakuda; Jun Hirata; Atsushi Baba; Akito Makino; Ryo Matsuyama; Ryan D White; Ryan Ρ Wurz; Youngsook Shin; Xiaoshan Min; Angel Guzman-Perez; Zhulun Wang; Antony Symons; Sanjay K Singh; Srinivasa Reddy Mothe; Sergei Belyakov; Anjan Chakrabarti; Satoshi Shuto

doi:10.1021/acsmedchemlett.9b00649

Discovery of [1,2,4]Triazolo[1,5- a]pyridine Derivatives as Potent and Orally Bioavailable RORγt Inverse Agonists

ACS Med Chem Lett. 2020 Feb 27;11(4):528-534. doi: 10.1021/acsmedchemlett.9b00649. eCollection 2020 Apr 9.

Authors

Ryota Nakajima¹, Hiroyuki Oono¹, Sakae Sugiyama¹, Yohei Matsueda¹, Tomohide Ida¹, Shinji Kakuda¹, Jun Hirata¹, Atsushi Baba¹, Akito Makino¹, Ryo Matsuyama¹, Ryan D White², Ryan Ρ Wurz³, Youngsook Shin³, Xiaoshan Min⁴, Angel Guzman-Perez², Zhulun Wang⁴, Antony Symons⁴, Sanjay K Singh⁵, Srinivasa Reddy Mothe⁵, Sergei Belyakov⁵, Anjan Chakrabarti⁵, Satoshi Shuto^{6

6}

Affiliations

¹ Teijin Institute for Bio-medical Research, Teijin Pharma Limited, 4-3-2 Asahigaoka, Hino, Tokyo 191-8512, Japan.
² Department of Medicinal Chemistry, Amgen Discovery Research, Amgen Inc., 360 Binney Street, Cambridge, Massachusetts 02142, United States.
³ Department of Medicinal Chemistry, Amgen Discovery Research, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
⁴ Department of Biologics, Department of Inflammation & Oncology Research, and Department of Molecular Engineering, Amgen Discovery Research, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
⁵ AMRI Singapore Research Centre, Pte. Ltd., 61 Science Park Road, #05-01 The Galen, Science Park III, Singapore 117525.
⁶ Faculty of Pharmaceutical Sciences and Center for Research and Education on Drug Discovery, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.

Abstract

The retinoic acid receptor-related orphan nuclear receptor γt (RORγt), 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 RORγt with 1a, an analogue of the known piperazine RORγt inverse agonist 1, triazolopyridine derivatives of 1 were designed and synthesized, and analogue 3a was found to be a potent RORγt 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)butanoyl)piperidin-4-yl)oxy)[1,2,4]triazolo[1,5-a]pyridin-6-yl)nicotinamide (5a), which exhibited strong RORγt 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.