The microbial metabolism of MK954 (Fig. 1), a novel nonpeptide angiotensin II receptor antagonist, was investigated using 40 microorganisms in an initial screen for cultures that will produce metabolites similar to those produced in the mammalianliver. The microbial transformation occurred under aerobic conditions in shake flasks incubated at 27°C. Three metabolites of MK954 were isolated and identified as the l'-hydroxy M2, 3'-hydroxy Ml5 and glucuronic acid conjugated M3derivatives. The structures of the metabolites were established by UV,^-NMRspectroscopy and FAB-MSspectrometry and are identical to metabolites produced by incubation of MK954 with mammalian liver slices.The renin-angiotensin system (RAS) plays a key role in the regulation of blood pressure and the etiology of hypertension. Angiotensin II (All) is the primary effector molecule of RAS. MK954 (Fig. 1) is an effective nonpeptidic anatagonist of the All receptor ATI, currently in Phase III clinical trials1~4). In the course of studying the metabolism of MK954, two hydroxylated compounds Mj and M2and a glucuronic acid conjugated metabolite M3were isolated as major metabolites5) from incubation with human liver slices.To facilitate further pharmacological and toxicological studies on these metabolites, we screened for microorganisms capable of metabolizing MK954 in the hope that compounds Ml9 M2 and M3 could be produced microbiologically.The present communication describes the microbial production of three mammalian metabolites of MK954 using three microorganisms: Actinoplanes sp. MA6559 (ATCC 53771), Streptomyces sp. MA6966 (ATCC 55293), and Streptomyces sp. MA6751 (ATCC 55043). Materials and Methods ChemicalsPhosphoric acid (Baker; Philipsburg, NJ) and all organic solvents (EM Science; Gibbstown, NJ) were HPLCgrade. Water was purified in a Millipore Milli-Q system (Bed ford, MA). Solvent for NMR analysis (CD3OD) was purchased from Aldrich Chemical (Millwaukee, WI). MK954 was prepared at DuPont/Merck Research Laboratories (Wilmington, DE).
The microbiological transformation of N-heptyl physostigmine (L-693,487) (1), a semisynthetic physostigmine cholinesterase inhibitor, was investigated using Verticillium lecanii MF 5713 (ATCC 74148), Acremonium sp MF 5723 (ATCC 74164) and Actinoplanes sp MA 6559 (ATCC 53771). Nine microbial metabolites (2-10) of 1 were isolated and purified using reversed-phase HPLC. The structures of the metabolites were established using spectroscopic techniques including MS and NMR. Some of the microbial metabolites were identical to metabolites present in urine of a dog treated with 1.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.