ABSTRACT
With the emergence and rapid spreading of NDM-1 and existence of clinically relevant VIM-1 and IMP-1, discovery of pan inhibitors targeting metallo-beta-lactamases (MBLs) became critical in our battle against bacterial infection. Concurrent with our fragment and high-throughput screenings, we performed a knowledge-based search of known metallo-beta-lactamase inhibitors (MBLIs) to identify starting points for early engagement of medicinal chemistry. A class of compounds exemplified by 11, discovered earlier as B. fragilis metallo-beta-lactamase inhibitors, was selected for in silico virtual screening. From these efforts, compound 12 was identified with activity against NDM-1 only. Initial exploration on metal binding design followed by structure-guided optimization led to the discovery of a series of compounds represented by 23 with a pan MBL inhibition profile. In in vivo studies, compound 23 in combination with imipenem (IPM) robustly lowered the bacterial burden in a murine infection model and became the lead for the invention of MBLI clinical candidates.
Subject(s)
Bacterial Infections , beta-Lactamase Inhibitors , Animals , Mice , beta-Lactamase Inhibitors/pharmacology , beta-Lactamase Inhibitors/therapeutic use , beta-Lactamase Inhibitors/chemistry , Imipenem/pharmacology , Imipenem/therapeutic use , beta-Lactamases/metabolism , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Anti-Bacterial Agents/chemistry , Microbial Sensitivity TestsABSTRACT
High throughput screening for ß-lactamase inhibitors afforded biphenyl hits such as 1. Hit confirmation and X-ray soaking experiments with Pseudomonas Aeruginosa AmpC enzyme led to the identification of an aryl boronic acid-serine complex 4, which was formed from phenyl boronic acid 8 (an impurity in compound 1) and ethylene glycol (the cryoprotectant in the soaking experiment).
Subject(s)
Bacterial Proteins/antagonists & inhibitors , Boronic Acids/chemistry , beta-Lactamase Inhibitors/chemistry , beta-Lactamases/chemistry , Bacterial Proteins/metabolism , Boronic Acids/chemical synthesis , Boronic Acids/metabolism , Drug Design , Pseudomonas aeruginosa/enzymology , beta-Lactamase Inhibitors/chemical synthesis , beta-Lactamase Inhibitors/metabolism , beta-Lactamases/metabolismABSTRACT
An analog of the thrombin receptor antagonist vorapaxar (SCH 530348) with increased aqueous solubility, compound 9c (SCH 602539), was discovered through incorporation of polar substituents on the pyridine ring of the himbacine-derived lead series. This analog retained the excellent potency, pharmacokinetic and safety properties of vorapaxar while increasing the aqueous solubility by 20-fold. Also presented are in vivo evaluations of this compound in a cynomolgus monkey platelet aggregation assay and in a Folts model of thrombosis in anesthetized monkeys.
Subject(s)
Lactones/chemistry , Platelet Aggregation Inhibitors/chemistry , Pyridines/chemistry , Water/chemistry , Animals , Drug Discovery , Humans , Inhibitory Concentration 50 , Lactones/pharmacology , Macaca fascicularis , Platelet Aggregation Inhibitors/pharmacology , Pyridines/pharmacology , Receptors, Thrombin/antagonists & inhibitors , SolubilityABSTRACT
The identity of the crystalline product formed by the acetylation of a mixture of methyl alpha- and beta-D-glucopyranuronates has been confirmed as being methyl 1,2,3,4-tetra-O-acetyl-beta-D-glucopyranuronate (3), which agrees with the assignment from 1H NMR. The absolute configuration of compound 3 was assigned to agree with the known chirality of the precursor sugar, D-glucono-6,3-lactone.
