Reddy, K. Raja , Totrov, Maxim , Lomovskaya, Olga, Griffith, David C. , Tarazi, Ziad , Clifton, Matt and Hecker, Scott J. (2022) Broad-spectrum cyclic boronate β-lactamase inhibitors featuring an intramolecular prodrug for oral bioavailability. Bioorganic & medicinal chemistry, 62. p. 116722. ISSN 1464-3391

Abstract

Early efforts to broaden the spectrum and potency of cyclic boronic acid β-lactamase inhibitor vaborbactam included a series of 7-membered ring boronates. Exploration of stereoisomers and incorporation of heteroatoms allowed identification of the all-carbon cyclic boronate with substituents trans as the preferred core structure, showing inhibition of Class A and C enzymes. Crystal structures of one analog bound to important β-lactamase enzymes were obtained. When isolated under acidic conditions, these compounds spontaneously formed a neutral cyclic anhydride (intramolecular prodrug) which was shown to have much-improved oral bioavailability (52-69%) compared to the ring-opened carboxylate salt (9%).

Item Type:	Article
Keywords:	Anti-Bacterial Agents Biological Availability Prodrugs beta-Lactamase Inhibitors beta-Lactamases
Date Deposited:	08 Jun 2022 00:45
Last Modified:	08 Jun 2022 00:45
URI:	https://oak.novartis.com/id/eprint/46667