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

Autor:	Yoon DS; Research and Early Development, Bristol Myers Squibb, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States., Liu C; Research and Early Development, Bristol Myers Squibb, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States., Jalagam PR; Biocon-Bristol Myers Squibb Research and Development Center, Bangalore 560099, India., Feng J; Research and Early Development, Bristol Myers Squibb, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States., Wang W; Research and Early Development, Bristol Myers Squibb, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States., Swidorski JJ; Research and Early Development, Bristol Myers Squibb, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States., Xu L; Research and Early Development, Bristol Myers Squibb, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States., Hartz RA; Research and Early Development, Bristol Myers Squibb, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States., Nair SK; Biocon-Bristol Myers Squibb Research and Development Center, Bangalore 560099, India., Beno BR; Research and Early Development, Bristol Myers Squibb, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States., Panda M; Biocon-Bristol Myers Squibb Research and Development Center, Bangalore 560099, India., Ghosh K; Biocon-Bristol Myers Squibb Research and Development Center, Bangalore 560099, India., Kumar A; Biocon-Bristol Myers Squibb Research and Development Center, Bangalore 560099, India., Sale H; Biocon-Bristol Myers Squibb Research and Development Center, Bangalore 560099, India., Shah D; Biocon-Bristol Myers Squibb Research and Development Center, Bangalore 560099, India., Mathur A; Research and Early Development, Bristol Myers Squibb, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States., Ellsworth BA; Research and Early Development, Bristol Myers Squibb, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States., Cheng D; Research and Early Development, Bristol Myers Squibb, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States., Regueiro-Ren A; Research and Early Development, Bristol Myers Squibb, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2024 Aug 22; Vol. 67 (16), pp. 14184-14199. Date of Electronic Publication: 2024 Aug 05.
DOI:	10.1021/acs.jmedchem.4c01008
Abstrakt:	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.
Databáze:	MEDLINE
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