Atropisomerism Observed in Galactose-Based Monosaccharide Inhibitors of Galectin-3 Comprising 2-Methyl-4-phenyl-2,4-dihydro-3H-1,2,4-triazole-3-thione
Year: 2024
Type: article
Abstract: 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 H -1,2,4-triazole-3-thione (compound 20 ) and 4-phenyl-4 H -1,2,4-triazole (compound 15 ). Notably, hindered rotation caused by steric interaction between the 3-thione and ortho -trifluoromethyl group of compounds 20, 21 induced formation of thermodynamically stable atropisomers. Distinct X-ray cocrystal structures of 20 and 21 were obtained, which clearly demonstrated that the configuration of 21 proscribes a key halogen bonding σ-hole interaction of 3-chloro with carbonyl oxygen of Gly182, thereby leading to significant loss in potency. Ultimately, 20 and 15 were evaluated in mouse pharmacokinetic studies, and both compounds exhibited oral exposures suitable for further in vivo assessment.
Source: Journal of Medicinal Chemistry
Authors: David S. Yoon, Chunjian Liu, Prasada Rao Jalagam, Jianxin Feng, Wei Wang, Jacob J. Swidorski, Li Xu, Richard A. Hartz, Satheesh K. Nair, Brett R. Beno, Manoranjan Panda, Kaushik Ghosh, Amit Kumar, Harinath Sale, Devang Shah, Arvind Mathur, Bruce A. Ellsworth, Dong Cheng, Alicia Regueiro-Ren
Institution: Bristol-Myers Squibb (United States)
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: green
OpenAlex ID: W4401324840