Identification\nof Novel Organo-Se BTSA-Based Derivatives\nas Potent, Reversible, and Selective PPARγ Covalent Modulators\nfor Antidiabetic Drug Discovery

Recent studies have identified selective peroxisome proliferator-activated\nreceptor γ (PPARγ) modulators, which synergistically engage\nin the inhibition mechanism of PPARγ-Ser273 phosphorylation,\nas a promising approach for developing safer and more effective antidiabetic\ndrugs. Herein, we present the design, synthesis, and evaluation of\na new class of organo-Se compounds, namely, benzothiaselenazole-1-oxides\n(BTSAs), acting as potent, reversible, and selective PPARγ covalent\nmodulators. Notably, <b>2n</b>, especially <b>(</b><i><b>R</b></i><b>)-2n</b>, displayed a high binding\naffinity and superior antidiabetic effects with diminished side effects.\nThis is mainly because it can reversibly form a unique covalent bond\nwith the Cys285 residue in PPARγ-LBD. Further mechanistic investigations\nrevealed that it manifested such desired pharmacological profiles\nprimarily by effectively suppressing PPARγ-Ser273 phosphorylation,\nenhancing glucose metabolism, and selectively upregulating the expression\nof insulin-sensitive genes. Collectively, our results suggest that <b>(</b><i><b>R</b></i><b>)-2n</b> holds promise\nas a lead compound for treating T2DM and also provides an innovative\nreversible covalent warhead reference for future covalent drug design.