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Publication Abstract from PubMed

A new series of orally available alpha-d-galactopyranosides with high affinity and specificity toward galectin-1 have been discovered. High affinity and specificity were achieved by changing six-membered aryl-triazolyl substituents in a series of recently published galectin-3-selective alpha-d-thiogalactosides (e.g., GB1107 K(d) galectin-1/3 3.7/0.037 muM) for five-membered heterocycles such as thiazoles. The in vitro pharmacokinetic properties were optimized, resulting in several galectin-1 inhibitors with favorable properties. One compound, GB1490 (K(d) galectin-1/3 0.4/2.7 muM), was selected for further characterization toward a panel of galectins showing a selectivity of 6- to 320-fold dependent on galectin. The X-ray structure of GB1490 bound to galectin-1 reveals the compound bound in a single conformation in the carbohydrate binding site. GB1490 was shown to reverse galectin-1-induced apoptosis of Jurkat cells at low muM concentrations. No cell cytotoxicity was observed for GB1490 up to 90 muM in the A549 cells. In pharmacokinetic studies in mice, GB1490 showed high oral bioavailability (F% > 99%).

Discovery of Selective and Orally Available Galectin-1 Inhibitors.,Zetterberg FR, Diehl C, Hakansson M, Kahl-Knutson B, Leffler H, Nilsson UJ, Peterson K, Roper JA, Slack RJ J Med Chem. 2023 Dec 28;66(24):16980-16990. doi: 10.1021/acs.jmedchem.3c01787. , Epub 2023 Dec 7. PMID:38059452^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.