Atropisomerism Observed in Galactose-Based Monosaccharide Inhibitors of Galectin-3 Comprising 2-Methyl-4-phenyl-2,4-dihydro-3<i>H</i>-1,2,4-triazole-3-thione

Galectin-3 (Gal-3) is a carbohydrate binding protein that has been implicated in the development and progression of fibrotic diseases. Proof-of-principal animal models have demonstrated that inhibition of Gal-3 is a potentially viable pathway for the treatment of fibrosis─with small molecule Gal-3 inhibitors advanced into clinical trials. We hereby report the discovery of novel galactose-based monosaccharide Gal-3 inhibitors comprising 2-methyl-4-phenyl-2,4-dihydro-3<i>H</i>-1,2,4-triazole-3-thione (compound <b>20</b>) and 4-phenyl-4<i>H</i>-1,2,4-triazole (compound <b>15</b>). Notably, hindered rotation caused by steric interaction between the 3-thione and <i>ortho</i>-trifluoromethyl group of compounds <b>20</b>, <b>21</b> induced formation of thermodynamically stable atropisomers. Distinct X-ray cocrystal structures of <b>20</b> and <b>21</b> were obtained, which clearly demonstrated that the configuration of <b>21</b> proscribes a key halogen bonding σ-hole interaction of 3-chloro with carbonyl oxygen of Gly182, thereby leading to significant loss in potency. Ultimately, <b>20</b> and <b>15</b> were evaluated in mouse pharmacokinetic studies, and both compounds exhibited oral exposures suitable for further <i>in vivo</i> assessment.