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Notable difference in anti-HIV activity of integrase inhibitors as a consequence of geometric and enantiomeric configurations

Authors
Journal
Bioorganic & Medicinal Chemistry Letters
0960-894X
Publisher
Elsevier
Publication Date
Volume
23
Issue
14
Identifiers
DOI: 10.1016/j.bmcl.2013.05.050
Keywords
  • Integrase
  • Anti-Hiv
  • Enantiomers
  • Drug Discovery
  • Cytochrome P450 Isozymes
Disciplines
  • Design

Abstract

Abstract While some examples are known of integrase inhibitors that exhibit potent anti-HIV activity, there are very few cases reported of integrase inhibitors that show significant differences in anti-HIV activity that result from distinctions in cis- and trans-configurations as well as enantiomeric stereostructure. We describe here the design and synthesis of two enantiomeric trans-hydroxycyclopentyl carboxamides which exhibit notable difference in anti-HIV activity. This difference is explained through their binding interactions within the active site of the HIV-1 integrase intasome. The more active enantiomer 3 (EC50 25nM) was relatively stable in human liver microsomes. Kinetic data revealed that its impact on key cytochrome P450 isozymes, as either an inhibitor or an activator, was minor, suggesting a favorable CYP profile.

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