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Structure-based amelioration of PXR transactivation in a novel series of macrocyclic allosteric inhibitors of HIV-1 integrase.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2020 Nov 15; Vol. 30 (22), pp. 127531. Date of Electronic Publication: 2020 Sep 02. - Publication Year :
- 2020
-
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.<br /> (Copyright © 2020 Elsevier Ltd. All rights reserved.)
- Subjects :
- Allosteric Regulation drug effects
Anti-HIV Agents chemical synthesis
Anti-HIV Agents chemistry
Cells, Cultured
Dose-Response Relationship, Drug
HIV Integrase Inhibitors chemical synthesis
HIV Integrase Inhibitors chemistry
Humans
Macrocyclic Compounds chemical synthesis
Macrocyclic Compounds chemistry
Microbial Sensitivity Tests
Molecular Structure
Pregnane X Receptor metabolism
Structure-Activity Relationship
Virus Replication drug effects
Anti-HIV Agents pharmacology
HIV Integrase Inhibitors pharmacology
HIV-1 drug effects
Macrocyclic Compounds pharmacology
Pregnane X Receptor antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 30
- Issue :
- 22
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 32890685
- Full Text :
- https://doi.org/10.1016/j.bmcl.2020.127531