Structure Guided Discovery of Novel Pan Metallo-β-Lactamase Inhibitors with Improved Gram-Negative Bacterial Cell Penetration.

Autor:	Dong S; Discovery Chemistry, Merck & Co., Inc., Rahway, New Jersey 07065, United States., Zhao Z; Discovery Chemistry, Merck & Co., Inc., Rahway, New Jersey 07065, United States., Tang H; Discovery Chemistry, Merck & Co., Inc., Rahway, New Jersey 07065, United States., Li G; Discovery Chemistry, Merck & Co., Inc., Rahway, New Jersey 07065, United States., Pan J; Discovery Chemistry, Merck & Co., Inc., Rahway, New Jersey 07065, United States., Gu X; Discovery Chemistry, Merck & Co., Inc., Rahway, New Jersey 07065, United States., Jiang J; Discovery Chemistry, Merck & Co., Inc., Rahway, New Jersey 07065, United States., Xiao L; Computational and Structural Chemistry, Merck & Co., Inc., Rahway, New Jersey 07065, United States., Scapin G; Computational and Structural Chemistry, Merck & Co., Inc., Rahway, New Jersey 07065, United States., Hunter DN; Discovery Chemistry, Merck & Co., Inc., Rahway, New Jersey 07065, United States., Yang D; Discovery Chemistry, Merck & Co., Inc., Rahway, New Jersey 07065, United States., Huang Y; Discovery Chemistry, Merck & Co., Inc., Rahway, New Jersey 07065, United States., Bennett F; Discovery Chemistry, Merck & Co., Inc., Rahway, New Jersey 07065, United States., Yang SW; Discovery Chemistry, Merck & Co., Inc., Rahway, New Jersey 07065, United States., Mandal M; Discovery Chemistry, Merck & Co., Inc., Rahway, New Jersey 07065, United States., Tang H; Discovery Chemistry, Merck & Co., Inc., Rahway, New Jersey 07065, United States., Su J; Discovery Chemistry, Merck & Co., Inc., Rahway, New Jersey 07065, United States., Tudge C; Discovery Chemistry, Merck & Co., Inc., Rahway, New Jersey 07065, United States., deJesus RK; Discovery Chemistry, Merck & Co., Inc., Rahway, New Jersey 07065, United States., Ding FX; Discovery Chemistry, Merck & Co., Inc., Rahway, New Jersey 07065, United States., Lombardo M; Discovery Chemistry, Merck & Co., Inc., Rahway, New Jersey 07065, United States., Hicks JD; Discovery Chemistry, Merck & Co., Inc., Rahway, New Jersey 07065, United States., Fischmann T; Computational and Structural Chemistry, Merck & Co., Inc., Rahway, New Jersey 07065, United States., Mirza A; Antibacterial/Antifungal, Merck & Co., Inc., West Point, Pennsylvania 19486, United States., Dayananth P; Quantitative Biosciences, Merck & Co., Inc., West Point, Pennsylvania 19486, United States., Painter RE; Quantitative Biosciences, Merck & Co., Inc., West Point, Pennsylvania 19486, United States., Villafania A; Quantitative Biosciences, Merck & Co., Inc., West Point, Pennsylvania 19486, United States., Garlisi CG; Quantitative Biosciences, Merck & Co., Inc., West Point, Pennsylvania 19486, United States., Zhang R; Quantitative Biosciences, Merck & Co., Inc., West Point, Pennsylvania 19486, United States., Mayhood TW; Quantitative Biosciences, Merck & Co., Inc., West Point, Pennsylvania 19486, United States., Si Q; Quantitative Biosciences, Merck & Co., Inc., West Point, Pennsylvania 19486, United States., Li N; Nonclinical Drug Safety, Merck & Co., Inc., West Point, Pennsylvania 19486, United States., Amin RP; Nonclinical Drug Safety, Merck & Co., Inc., West Point, Pennsylvania 19486, United States., Bhatt B; Nonclinical Drug Safety, Merck & Co., Inc., West Point, Pennsylvania 19486, United States., Chen F; Nonclinical Drug Safety, Merck & Co., Inc., West Point, Pennsylvania 19486, United States., Regan CP; Nonclinical Drug Safety, Merck & Co., Inc., West Point, Pennsylvania 19486, United States., Regan H; Nonclinical Drug Safety, Merck & Co., Inc., West Point, Pennsylvania 19486, United States., Lin X; Pharmacokinetics Pharmacodynamics and Drug Metabolism, Merck & Co., Inc., Rahway, New Jersey 07065, United States., Wu J; Pharmacokinetics Pharmacodynamics and Drug Metabolism, Merck & Co., Inc., Rahway, New Jersey 07065, United States., Leithead A; Discovery Pharmaceutical Sciences, Merck & Co., Inc., West Point, Pennsylvania 19486, United States., Pollack SR; Discovery Process Chemistry, Merck & Co., Inc., Rahway, New Jersey 07065, United States., Scott JD; Discovery Chemistry, Merck & Co., Inc., Rahway, New Jersey 07065, United States., Nargund RP; Discovery Chemistry, Merck & Co., Inc., Rahway, New Jersey 07065, United States., Therien AG; Exploratory Science Center, Merck & Co., Inc., Cambridge, Massachusetts 02139, United States., Black T; Antibacterial/Antifungal, Merck & Co., Inc., West Point, Pennsylvania 19486, United States., Young K; Antibacterial/Antifungal, Merck & Co., Inc., West Point, Pennsylvania 19486, United States., Pasternak A; Discovery Chemistry, Merck & Co., Inc., Rahway, New Jersey 07065, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2024 Mar 14; Vol. 67 (5), pp. 3400-3418. Date of Electronic Publication: 2024 Feb 22.
DOI:	10.1021/acs.jmedchem.3c01614
Abstrakt:	The use of β-lactam (BL) and β-lactamase inhibitor combination to overcome BL antibiotic resistance has been validated through clinically approved drug products. However, unmet medical needs still exist for the treatment of infections caused by Gram-negative (GN) bacteria expressing metallo-β-lactamases. Previously, we reported our effort to discover pan inhibitors of three main families in this class: IMP, VIM, and NDM. Herein, we describe our work to improve the GN coverage spectrum in combination with imipenem and relebactam. This was achieved through structure- and property-based optimization to tackle the GN cell penetration and efflux challenges. A significant discovery was made that inhibition of both VIM alleles, VIM-1 and VIM-2, is essential for broad GN coverage, especially against VIM-producing P. aeruginosa . In addition, pharmacokinetics and nonclinical safety profiles were investigated for select compounds. Key findings from this drug discovery campaign laid the foundation for further lead optimization toward identification of preclinical candidates.
Databáze:	MEDLINE
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