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

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.
Ryota Nakajima 1,  Hiroyuki Oono 1,  Sakae Sugiyama 1,  Yohei Matsueda 1,  Tomohide Ida 1,  Shinji Kakuda 1,  Jun Hirata 1,  Atsushi Baba 1,  Akito Makino 1,  Ryo Matsuyama 1,  Ryan D White 2,  Ryan Ρ Wurz 3,  Youngsook Shin 3,  Xiaoshan Min 4,  Angel Guzman-Perez 2,  Zhulun Wang 4,  Antony Symons 4,  Sanjay K Singh 5,  Srinivasa Reddy Mothe 5,  Sergei Belyakov 5,  Anjan Chakrabarti 5,  Satoshi Shuto 6 6
Affiliations

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.
PMID: 32292560 DOI: 10.1021/acsmedchemlett.9b00649
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.

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