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

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

doi:10.1016/j.bmcl.2020.127531

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

Bioorg Med Chem Lett. 2020 Nov 15;30(22):127531. doi: 10.1016/j.bmcl.2020.127531. Epub 2020 Sep 2.

Authors

Prasanna Sivaprakasam¹, Zhongyu Wang², Nicholas A Meanwell², Javed A Khan³, David R Langley⁴, Stephen R Johnson³, Guo Li², Annapurna Pendri², Timothy P Connolly², Mian Gao⁵, Daniel M Camac³, Cheryl Klakouski⁶, Tatyana Zvyaga⁶, Christopher Cianci⁷, Brian McAuliffe⁷, Bo Ding⁷, Linda Discotto⁷, Mark R Krystal⁷, Susan Jenkins⁸, Kevin M Peese², B Narasimhulu Naidu²

Affiliations

¹ Computer-Aided Drug Design, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA. Electronic address: [email protected].
² Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
³ Molecular Structure & Design, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543-4000, USA.
⁴ Computer-Aided Drug Design, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
⁵ Protein Sciences, Bristol-Myers Squibb Research and Development, P.O. Box 4000, Princeton, NJ 08543-4000, USA.
⁶ Lead Discovery and Optimization, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
⁷ Virology Discovery Biology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
⁸ Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.

PMID: 32890685
DOI: 10.1016/j.bmcl.2020.127531

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.

Keywords: ALLINI; HIV-1 integrase; Inhibitor; LEDGF/p75; Macrocycle; PXR.

MeSH terms

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

Substances

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