Design, Synthesis, and Anti-Inflammatory Evaluation of a Novel PPARδ Agonist with a 4-(1-Pyrrolidinyl)piperidine Structure

  • J Med Chem. 2023 Aug 24;66(16):11428-11446. doi: 10.1021/acs.jmedchem.3c00932.
Terukazu Kato  1 ,  Keita Fukao  1 ,  Takafumi Ohara  1 ,  Noriyuki Naya  1 ,  Ryukou Tokuyama  2 ,  Susumu Muto  2 ,  Hiroshi Fukasawa  2 ,  Akiko Itai  2 ,  Ken-Ichi Matsumura  1
Affiliations
  • 1. Shionogi Pharmaceutical Research Center, Shionogi & Co., Ltd., Toyonaka, Osaka 561-0825, Japan.
  • 2. Institute of Medicinal Molecular Design, Inc., Tokyo 113-0033, Japan.
PMID: 37552807 DOI: 10.1021/acs.jmedchem.3c00932
Abstract

Peroxisome Proliferator-activated Receptor δ (PPARδ) is considered to be a pharmaceutical target to treat metabolic diseases including atherosclerosis, but there is no PPARδ Agonist available for clinical use. We have previously reported the discovery of piperidinyl/piperazinyl benzothiazole derivatives as a new series of PPARδ agonists using docking-based virtual screening methods. In the present study, we found that introduction of a pyrrolidine group into the 4-position of their central piperidine rings enhances hPPARδ activity and subtype selectivity. This led to the discovery of 21 having strong PPARδ Agonist activity (EC50 = 3.6 nM) with excellent ADME properties. Furthermore, 21 significantly suppressed atherosclerosis progression by 50-60% with reduction of the serum level of MCP-1 in LDLr-KO mice.

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