Side chain SAR of bicyclic beta-lactamase inhibitors (BLIs). 1. Discovery of a class C BLI for combination with imipinem

Timothy A Blizzard; Helen Chen; Seongkon Kim; Jane Wu; Katherine Young; Young-Whan Park; Amy Ogawa; Susan Raghoobar; Ronald E Painter; Nichelle Hairston; Sang Ho Lee; Andrew Misura; Tom Felcetto; Paula Fitzgerald; Nandini Sharma; Jun Lu; Sookhee Ha; Emily Hickey; Jeff Hermes; Milton L Hammond

doi:10.1016/j.bmcl.2009.12.069

Side chain SAR of bicyclic beta-lactamase inhibitors (BLIs). 1. Discovery of a class C BLI for combination with imipinem

Bioorg Med Chem Lett. 2010 Feb 1;20(3):918-21. doi: 10.1016/j.bmcl.2009.12.069. Epub 2009 Dec 23.

Affiliation

¹ Department of Medicinal Chemistry, Merck Research Labs, Rahway, NJ 07065, USA. tim_blizzard@merck.com

PMID: 20044254
DOI: 10.1016/j.bmcl.2009.12.069

Abstract

Bridged monobactam beta-lactamase inhibitors were prepared and evaluated as potential partners for combination with imipenem to overcome class C beta-lactamase mediated resistance. The (S)-azepine analog 2 was found to be effective in both in vitro and in vivo assays and was selected for preclinical development.

Publication types

Comparative Study

MeSH terms

Animals
Bridged Bicyclo Compounds, Heterocyclic / chemistry
Bridged Bicyclo Compounds, Heterocyclic / pharmacology
Carbapenems / chemistry*
Carbapenems / pharmacology
Drug Combinations
Drug Discovery / methods*
Imipenem / chemistry*
Imipenem / pharmacology
Mice
Pseudomonas Infections / drug therapy
Pseudomonas Infections / enzymology
Pseudomonas aeruginosa / drug effects
Pseudomonas aeruginosa / physiology
Structure-Activity Relationship
beta-Lactam Resistance / drug effects
beta-Lactam Resistance / physiology
beta-Lactamase Inhibitors*
beta-Lactamases / metabolism

Substances

Bridged Bicyclo Compounds, Heterocyclic
Carbapenems
Drug Combinations
beta-Lactamase Inhibitors
Imipenem
beta-Lactamases