Design,Synthesis And SAR Analysis Of Novel Prostaglandin EP4 Antagonist Based On A Scaffold Of Nonaromatic Ring Fused To Thiophene Carboxamido-benzoic Acid

Prostaglandin E2(PGE2)has a number of biological functions,and elicits its biological actions via four specific PGE2 receptor EP subtypes(EP1 to EP4).EP4 receptor is expressed in a variety of organs,and involved in a very wide range of physiological processes.More and more scientific evidences suggest that a highly selective EP4 antagonist could be an effective drug to relieve inflammatory pain and with a better gastrointestinal(GI)tolerability.Rencently,EP4 receptor has been demonstrated to be implicated in tumor progression,and playing important roles in the field of cancer therapy.After many years of research,many selective and potent EP4 antagonists have entered clinical trials.The first-generation EP4 antagonist containing acylsulfonamide could result in a species dependent hydrolysis of acyl sulfonamide moiety,leading to a drawback of variable pharmacological effects in preclinical species.In this paper,a new series of potent and selective EP4 antagonist based on the carboxamido-benzoic acid scafford containing the nonaromatic ring fused to thiophene substituted structure,which is chemically similar to the second-generation EP4 antagonists,have been designed and synthesized.The efficient and reliable chemical synthesis methods of these derivatives have been developed.According to the screening of the antagonist activities and the SAR analysis of the compounds,the carboxamido-benzoic acid derivatives containing tetrahydropyran fused to thiophene substituted structure have been demonstrated to be novel EP4 antagonists with improved antagonist activities and physicochemical properties.The compounds C11,C16 and C17,which showed higher antagonist activities compared with E7046(positive control),high selectivities for EP4 receptor and low toxicity,would become competitive candidate compounds.