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

Abstract Herein we described the design, synthesis and evaluation of a novel series of benzo[ d ]thiazole derivatives toward an orally active EP 1 antagonist. Lead generation studies provided benzo[ d ]thiazole core from the four designed scaffolds. Optimization of this scaffold in terms of EP 1 antagonist potency and ligand-lipophilicity efficiency (LLE; pIC 50 -clogP) led to a 1,2,3,6-tetrahydropyridyl-substituted benzo[ d ]thiazole derivative, 7r (IC 50 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.