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Bioorg Med Chem Lett. 2012 Jan 1;22(1):85-9. doi: 10.1016/j.bmcl.2011.11.071. Epub 2011 Nov 23.

Discovery of bacterial NAD⁺-dependent DNA ligase inhibitors: improvements in clearance of adenosine series.

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1
Infection Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA. suzanne.stokes@astrazeneca.com

Abstract

Optimization of clearance of adenosine inhibitors of bacterial NAD(+)-dependent DNA ligase is discussed. To reduce Cytochrome P-450-mediated metabolic clearance, many strategies were explored; however, most modifications resulted in compounds with reduced antibacterial activity and/or unchanged total clearance. The alkyl side chains of the 2-cycloalkoxyadenosines were fluorinated, and compounds with moderate antibacterial activity and favorable pharmacokinetic properties in rat and dog were identified.

PMID:
22154350
DOI:
10.1016/j.bmcl.2011.11.071
[Indexed for MEDLINE]
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