Structure-based amelioration of PXR transactivation in a novel series of macrocyclic allosteric inhibitors of HIV-1 integrase.

Abstract

Previous studies have identified a series of imidazo[1,2-a]pyridine (IZP) derivatives as potent allosteric inhibitors of HIV-1 integrase (ALLINIs) and virus infection in cell culture. However, IZPs were also found to be relatively potent activators of the pregnane-X receptor (PXR), raising the specter of induction of CYP-mediated drug disposition pathways. In an attempt to modify PXR activity without affecting anti-HIV-1 activity, rational structure-based design and modeling approaches were used. An X-ray cocrystal structure of (S,S)-1 in the PXR ligand binding domain (LBD) allowed an examination of the potential of rational structural modifications designed to abrogate PXR. The introduction of bulky basic amines at the C-8 position provided macrocyclic IZP derivatives that displayed potent HIV-1 inhibitory activity in cell culture with no detectable PXR transactivation at the highest concentration tested.

• Authors: Prasanna Sivaprakasam, Zhongyu Wang, Nicholas A Meanwell, Javed A Khan, David R Langley, Stephen R Johnson, Guo Li, Annapurna Pendri, Timothy P Connolly, Mian Gao, Daniel M Camac, Cheryl Klakouski, Tatyana Zvyaga, Christopher Cianci, Brian McAuliffe, Bo Ding, Linda Discotto, Mark R Krystal, Susan Jenkins, Kevin M Peese, B Narasimhulu Naidu
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 30 Issue 22 Pg. 127531 (11 15 2020) ISSN: 1464-3405 [Electronic] England
• PMID: 32890685 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier Ltd. All rights reserved.

Chemical References

• Anti-HIV Agents
• HIV Integrase Inhibitors
• Macrocyclic Compounds
• Pregnane X Receptor

Topics

• Allosteric Regulation (drug effects)
• Anti-HIV Agents (chemical synthesis, chemistry, pharmacology)
• Cells, Cultured
• Dose-Response Relationship, Drug
• HIV Integrase Inhibitors (chemical synthesis, chemistry, pharmacology)
• HIV-1 (drug effects)
• Humans
• Macrocyclic Compounds (chemical synthesis, chemistry, pharmacology)
• Microbial Sensitivity Tests
• Molecular Structure
• Pregnane X Receptor (antagonists & inhibitors, metabolism)
• Structure-Activity Relationship
• Virus Replication (drug effects)