Discovery of a novel 2-(1 H -pyrazolo[3,4- b ]pyridin-1-yl)thiazole derivative as an EP 1 receptor antagonist and in vivo studies in a bone fracture model

Abstract We describe a medicinal chemistry approach to the discovery of a novel EP 1 antagonist exhibiting high potency and good pharmacokinetics. Our starting point is 1 , an EP 1 receptor antagonist that exhibits pharmacological efficacy in cystometry models following intravenous administration. Despite its good potency in vitro , the high lipophilicity of 1 is a concern in long-term in vivo studies. Further medicinal chemistry efforts identified 4 as an improved lead compound with good in vitro ADME profile applicable to long term in vivo studies. A rat fracture study was conducted with 4 for 4 weeks to validate its utility in bone fracture healing. The results suggest that this EP 1 receptor antagonist stimulates callus formation and thus 4 has potential for enhancing fracture healing.