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

Herein we described the design, synthesis and evaluation of a novel series of benzo[d]thiazole derivatives toward an orally active EPi 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 ligandlipophilicity efficiency (LLE; pIC(50)-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. (C) 2017 Elsevier Ltd. All rights reserved.