Discovery of 6-Oxo-4-phenyl-hexanoic acid derivatives as RORγt inverse agonists showing favorable ADME profile

Ryota Nakajima; Hiroyuki Oono; Keiko Kumazawa; Tomohide Ida; Jun Hirata; Ryan D White; Xiaoshan Min; Angel Guzman-Perez; Zhulun Wang; Antony Symons; Sanjay K Singh; Srinivasa Reddy Mothe; Sergei Belyakov; Anjan Chakrabarti; Satoshi Shuto

doi:10.1016/j.bmcl.2021.127786

Discovery of 6-Oxo-4-phenyl-hexanoic acid derivatives as RORγt inverse agonists showing favorable ADME profile

Bioorg Med Chem Lett. 2021 Mar 15:36:127786. doi: 10.1016/j.bmcl.2021.127786. Epub 2021 Jan 23.

Authors

Affiliations

¹ Teijin Institute for Bio-medical Research, Teijin Pharma Limited, 4-3-2 Asahigaoka, Hino, Tokyo 191-8512, Japan. Electronic address: [email protected].
² Teijin Institute for Bio-medical Research, Teijin Pharma Limited, 4-3-2 Asahigaoka, Hino, Tokyo 191-8512, Japan.
³ Department of Medicinal Chemistry, Amgen Discovery Research, Amgen Inc., 360 Binney Street, Cambridge, MA 02142, United States.
⁴ Departments of Molecular Engineering, Amgen Discovery Research, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, United States.
⁵ Departments of Inflammation & Oncology Research Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, United States.
⁶ AMRI Singapore Research Centre, Pte. Ltd., 61 Science Park Road, #05-01 The Galen, Science Park III, Singapore 117525, Singapore.
⁷ Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan; Center for Research and Education on Drug Discovery, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan. Electronic address: [email protected].

PMID: 33493627
DOI: 10.1016/j.bmcl.2021.127786

Abstract

The retinoic acid receptor-related orphan nuclear receptor gamma t (RORγt), which is a promising therapeutic target for immune diseases, is a major transcription factor of genes related to psoriasis pathogenesis, such as interleukin (IL)-17A, IL-22, and IL-23R. Inspired by the co-crystal structure of RORγt, a 6-oxo-4-phenyl-hexanoic acid derivative 6a was designed, synthesized, and identified as a ligand of RORγt. The structure-activity relationship (SAR) studies in 6a, which focus on the improvement of its membrane permeability profile by introducing chlorine atoms, led to finding 12a, which has a potent RORγt inhibitory activity and a favorable pharmacokinetic profile.

Keywords: Inverse agonist; Nuclear receptor; RORγt.

MeSH terms

Animals
Caproates / chemistry
Caproates / metabolism
Caproates / pharmacology*
Dose-Response Relationship, Drug
Drug Discovery*
Humans
Mice
Microsomes, Liver / chemistry
Microsomes, Liver / metabolism
Molecular Structure
Nuclear Receptor Subfamily 1, Group F, Member 3 / agonists*
Nuclear Receptor Subfamily 1, Group F, Member 3 / genetics
Structure-Activity Relationship

Substances

Caproates
Nuclear Receptor Subfamily 1, Group F, Member 3
hexanoic acid