Novel N-Linked Aminopiperidine Inhibitors of Bacterial Topoisomerase Type II with Reduced pK(a): Antibacterial Agents with an Improved Safety Profile.

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Novel N-Linked Aminopiperidine Inhibitors of Bacterial Topoisomerase Type II with Reduced pK(a): Antibacterial Agents with an Improved Safety Profile.

J Med Chem. 2012 Aug 9;55(15):6916-33

Authors: Reck F, Alm RA, Brassil P, Newman JV, Ciaccio P, McNulty J, Barthlow H, Goteti K, Breen J, Comita-Prevoir J, Cronin M, Ehmann DE, Geng B, Godfrey AA, Fisher SL

Abstract
Novel non-fluoroquinolone inhibitors of bacterial type II topoisomerases (DNA gyrase and topoisomerase IV) are of interest for the development of new antibacterial agents that are not impacted by target-mediated cross-resistance with fluoroquinolones. N-Linked amino piperidines, such as 7a, generally show potent antibacterial activity, including against quinolone-resistant isolates, but suffer from hERG inhibition (IC(50) = 44 ?M for 7a) and QT prolongation in vivo. We now disclose the finding that new analogues of 7a with reduced pK(a) due to substitution with an electron-withdrawing substituent in the piperidine moiety, such as R,S-7c, retained the Gram-positive activity of 7a but showed significantly less hERG inhibition (IC(50) = 233 ?M for R,S-7c). This compound exhibited moderate clearance in dog, promising efficacy against a MRSA strain in a mouse infection model, and an improved in vivo QT profile as measured in a guinea pig in vivo model. As a result of its promising activity, R,S-7c was advanced into phase I clinical studies.

PMID: 22779424 [PubMed - in process]

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