Discovery and structure-activity relationship study of 2-piperazinyl-benzothiazole derivatives as potent and selective PPARδ agonists

Kato, Terukazu; Ohara, Takafumi; Suzuki, Naoyuki; Naya, Noriyuki; Fukao, Keita; Tokuyama, Ryukou; Muto, Shoshi; Fukasawa, Hiroshi; Itai, Akiko; Matsumura, Ken‐ichi

doi:10.1016/j.bmc.2023.117215

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“…Recently we have reported the discovery of piperidinyl/ piperazinyl benzothiazole derivatives as a new series of PPARδ agonists, including compound 1, by utilizing docking-based virtual screening methods (Figure 1). 29,30 These compounds showed high agonist activity for PPARδ and subtype selectivity and also led to significant elevation of the HDL-C level in a mouse model. Here, we describe our further optimization study of lead compound 1 to develop a more promising PPARδ agonist 21 with good ADME (absorption, distribution, metabolism, and excretion) profiles.…”

Section: ■ Introductionmentioning

confidence: 99%

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

et al. 2023

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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 (EC 50 = 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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Section: ■ Introductionmentioning

confidence: 99%