Discovery of orally effective and safe GPR40 agonists by incorporating a chiral, rigid and polar sulfoxide into β-position to the carboxylic acid

GPR40 is primarily expressed in pancreatic islet β-cells, and its activation by endogenous ligands of medium to long-chain free fatty acids or synthetic agonists is clinically proved to improve glycemic control by stimulating glucose-dependent insulin secretion. However, most of the reported agonists are highly lipophilic, which might cause lipotoxicity and the off-target effects in CNS. Particularly, the withdrawal of TAK-875 from clinical trials phase III due to liver toxicity concern threw doubt over the long-term safety of targeting GPR40. Improving the efficacy and the selectivity, thus enlarging the therapeutic window would provide an alternative to develop safe GPR40-targeted therapeutics. Herein, by employing an innovative “three-in-one” pharmacophore drug design strategy, the optimal structural features for GPR40 agonist was integrated into one functional group of sulfoxide, which was incorporated into the β-position of the propanoic acid core pharmacophore. As a result, the conformational constraint, polarity as well as chirality endowed by the sulfoxide significantly enhanced the efficacy, selectivity and ADMET properties of the novel (S)- 2-(phenylsulfinyl)acetic acid-based GPR40 agonists. The lead compounds (S)-4a and (S)-4s exhibited robust plasma glucose-lowering effects and insulinotropic action during an oral glucose tolerance test in C57/BL6 mice, excellent pharmacokinetic profile and little hepatobiliary transporter inhibition, marginal cell toxicities against human primary hepatocyte at 100 μM. [Display omitted] •An innovative “three-in-one” pharmacophore concept for the drug-like GPR40 agonist design.•Optimal structural features for GPR40 agonist integrated into one functional group of the sulfoxide.•The chiral, rigid and polar sulfoxide at β-position to the propanoic acid core favoring the efficacy, safety and selectivity.•The novel (S)- 2-(phenylsulfinyl)acetic acid-based GPR40 agonists revealing remarkably reduced risk of hepatotoxicity.•The (S)-sulfoxide containing GPR40 agonists exhibiting excellent PK profile and plasma glucose-lowering effect in vivo.