Shionogi Pharmaceutical Research Center, Shionogi & Co., Ltd., Toyonaka, Osaka 561-0825, Japan.
Institute of Medicinal Molecular Design, Inc., Tokyo 113-0033, Japan.
J Med Chem. 2023 Aug 24;66(16):11428-11446. doi: 10.1021/acs.jmedchem.3c00932. Epub 2023 Aug 8.
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 having strong PPARδ agonist activity (EC = 3.6 nM) with excellent ADME properties. Furthermore, significantly suppressed atherosclerosis progression by 50-60% with reduction of the serum level of MCP-1 in LDLr-KO mice.
过氧化物酶体增殖物激活受体 δ (PPARδ) 被认为是治疗包括动脉粥样硬化在内的代谢疾病的药物靶点，但目前尚无可用于临床的 PPARδ 激动剂。我们之前曾报道过使用基于对接的虚拟筛选方法发现哌啶基/哌嗪基苯并噻唑衍生物作为一类新的 PPARδ 激动剂。在本研究中，我们发现将吡咯烷基团引入其中心哌啶环的 4-位可增强 hPPARδ 的活性和亚型选择性。这导致发现了具有强 PPARδ 激动剂活性（EC = 3.6 nM）和优异的 ADME 特性的 。此外， 可显著抑制 LDLr-KO 小鼠的动脉粥样硬化进展，使 MCP-1 血清水平降低 50-60%。
