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ID: ALA5260859
Journal: Bioorg Med Chem
Title: Discovery and structure-activity relationship study of 2-piperazinyl-benzothiazole derivatives as potent and selective PPARδ agonists.
Authors: Kato T, Ohara T, Suzuki N, Naya N, Fukao K, Tokuyama R, Muto S, Fukasawa H, Itai A, Matsumura KI.
Abstract: Peroxisome proliferator-activated receptor δ (PPARδ) is considered to be a target for treating metabolic syndrome, whereas there is no PPARδ agonist in clinical use. Previously, we have reported the discovery of 2-(1-piperidinyl)-1,3-benzothiazole derivatives as a new series of PPARδ agonists using docking-based virtual screening techniques. In this study, we performed the further optimization study of the lead compound 1 focusing on improvement of hydrophobic interactions in the binding site to enhance agonist efficacy for PPARδ and subtype selectivity, thereby discovering a novel PPARδ agonist 5g which exhibited high in vitro agonist activity (hPPARδ, EC50 = 4.1 nM) and sufficiently high selectivity ratio over PPARα and PPARγ. Moreover, 5g revealed a significant upregulation of high-density lipoprotein cholesterol level in vivo.
CiteXplore: 36840990