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Synthesis, Structure, and SAR of Tetrahydropyran-Based LpxC Inhibitors.

ABSTRACT: In the search for novel Gram-negative agents, we performed a comprehensive search of the AstraZeneca collection and identified a tetrahydropyran-based matrix metalloprotease (MMP) inhibitor that demonstrated nanomolar inhibition of UDP-3-O-(acyl)-N-acetylglucosamine deacetylase (LpxC). Crystallographic studies in Aquifex aeolicus LpxC indicated the tetrahydropyran engaged in the same hydrogen bonds and van der Waals interactions as other known inhibitors. Systematic optimization of three locales on the scaffold provided compounds with improved Gram-negative activity. However, the optimization of LpxC activity was not accompanied by reduced inhibition of MMPs. Comparison of the crystal structure of the native product, UDP-3-O-(acyl)-glucosamine, in Aquifex aeolicus to the structure of a tetrahydropyran-based inhibitor indicates pathways for future optimization.

SUBMITTER: Murphy-Benenato KE

PROVIDER: S-EPMC4233352 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Synthesis, Structure, and SAR of Tetrahydropyran-Based LpxC Inhibitors.

Murphy-Benenato Kerry E KE Olivier Nelson N Choy Allison A Ross Philip L PL Miller Matthew D MD Thresher Jason J Gao Ning N Hale Michael R MR

ACS medicinal chemistry letters 20140923 11

In the search for novel Gram-negative agents, we performed a comprehensive search of the AstraZeneca collection and identified a tetrahydropyran-based matrix metalloprotease (MMP) inhibitor that demonstrated nanomolar inhibition of UDP-3-O-(acyl)-N-acetylglucosamine deacetylase (LpxC). Crystallographic studies in Aquifex aeolicus LpxC indicated the tetrahydropyran engaged in the same hydrogen bonds and van der Waals interactions as other known inhibitors. Systematic optimization of three locales ...[more]

PMID: 25408833

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