Synthesis and evaluation of a potent, well-balanced EP 2 /EP 3 dual agonist

Abstract A highly potent and well-balanced dual agonist for the EP 2 and EP 3 receptors is described. Optimization of the lead compound was accomplished in consideration of the relative agonist activity against each EP subtype receptor and the pharmacokinetic profile. As the result, 2-[(2-{(1 R ,2 R )-2-[(1 E ,4 S )-5-cyclopentyl-4-hydroxy-4-methyl-1-penten-1-yl]-5-oxocyclopentyl}eth-yl)thio]-1,3-thiazole-4-carboxylic acid ( 10 ) showed excellent potency (human EC 50 EP 2  = 1.1 nM, EP 3  = 1.0 nM) with acceptable selectivity over the EP 1 and EP 4 subtypes (>2000-fold). Further fine-tuning of compound 10 led to identification of ONO-8055 as a clinical candidate. ONO-8055 was effective at an extremely low dose (0.01 mg/kg, po, bid) in rats, and dose-dependently improved voiding dysfunction in a monkey model of underactive bladder (UAB). ONO-8055 is expected to be a novel and highly promising drug for UAB.