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
  • 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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