(S)-4a

(S)-4a is a novel, orally effective small molecule GPR40 agonist developed using an innovative "three-in-one" pharmacophore drug design strategy. It incorporates a chiral, rigid, and polar sulfoxide into the β-position of a propanoic acid core, which significantly enhances its efficacy, selectivity, and ADMET properties. The drug is designed to improve glycemic control by stimulating glucose-dependent insulin secretion, making it a potential therapeutic for type 2 diabetes mellitus. Preclinical studies in C57/BL6 mice demonstrated robust plasma glucose-lowering effects and insulinotropic action, along with an excellent pharmacokinetic profile, minimal hepatobiliary transporter inhibition, and marginal cell toxicities against human primary hepatocytes.