Identification of novel 1,2,3,6-tetrahydropyridyl-substituted benzo[d]thiazoles: lead generation and optimization toward potent and orally active EP1 receptor antagonists

Publication date: Available online 26 April 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Kentaro Umei, Yosuke Nishigaya, Kazuya Tatani, Yasushi Kohno, Nobuyuki Tanaka, Shigeki Seto
Herein we described the design, synthesis and evaluation of a novel series of benzo[d]thiazole derivatives toward an orally active EP1 antagonist. Lead generation studies provided benzo[d]thiazole core from the four designed scaffolds. Optimization of this scaffold in terms of EP1 antagonist potency and ligand-lipophilicity efficiency (LLE; pIC50-clogP) led to a 1,2,3,6-tetrahydropyridyl-substituted benzo[d]thiazole derivative, 7r (IC50 1.1 nM; LLE 4.7), which showed a good pharmacological effect when administered intraduodenally in a 17-phenyl trinor-PGE2 (17-PTP)-induced overactive bladder model in rats.

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