Design, synthesis and SAR study of novel C2-pyrazolopyrimidine amides and amide isosteres as allosteric integrase inhibitors

Manoj Patel; Christopher Cianci; Christopher W Allard; Dawn D Parker; Jean Simmermacher; Susan Jenkins; Brian Mcauliffe; Beatrice Minassian; Linda Discotto; Mark Krystal; Nicholas A Meanwell; B Narasimhulu Naidu

doi:10.1016/j.bmcl.2020.127516

Design, synthesis and SAR study of novel C2-pyrazolopyrimidine amides and amide isosteres as allosteric integrase inhibitors

Bioorg Med Chem Lett. 2020 Nov 1;30(21):127516. doi: 10.1016/j.bmcl.2020.127516. Epub 2020 Aug 27.

Affiliations

¹ Departments of Discovery Chemistry and Molecular Technologies, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA; ViiV Healthcare, 36 East Industrial Parkway, Branford, CT 06405, USA. Electronic address: [email protected].
² Virology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
³ Departments of Discovery Chemistry and Molecular Technologies, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
⁴ Departments of Discovery Chemistry and Molecular Technologies, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA; ViiV Healthcare, 36 East Industrial Parkway, Branford, CT 06405, USA.
⁵ Virology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA; ViiV Healthcare, 36 East Industrial Parkway, Branford, CT 06405, USA.

PMID: 32860982
DOI: 10.1016/j.bmcl.2020.127516

Abstract

The design, synthesis and structure-activity relationships associated with a series of C2-substituted pyrazolopyrimidines as potent allosteric inhibitors of HIV-1 integrase (ALLINIs) are described. Structural modifications to these molecules were made in order to examine the effect on potency and, for select compounds, pharmacokinetic properties. We examined a variety of C2-substituted pyrazolopyrimidines and found that the C2-amide derivatives demonstrated the most potent antiviral activity of this class against HIV-1 infection in cell culture.

Keywords: Allosteric integrase inhibitors; HIV; HIV-1 integrase; LEDGF/p75; Pyrazolopyrimidine.

MeSH terms

Allosteric Regulation / drug effects
Amides / chemical synthesis
Amides / chemistry
Amides / pharmacology*
Anti-HIV Agents / chemical synthesis
Anti-HIV Agents / chemistry
Anti-HIV Agents / pharmacology*
Cells, Cultured
Dose-Response Relationship, Drug
Drug Design
HIV Integrase / metabolism*
HIV Integrase Inhibitors / chemical synthesis
HIV Integrase Inhibitors / chemistry
HIV Integrase Inhibitors / pharmacology*
HIV-1 / drug effects
HIV-1 / metabolism
Humans
Microbial Sensitivity Tests
Molecular Structure
Pyrazoles / chemical synthesis
Pyrazoles / chemistry
Pyrazoles / pharmacology*
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Structure-Activity Relationship

Substances

Amides
Anti-HIV Agents
HIV Integrase Inhibitors
Pyrazoles
Pyrimidines
HIV Integrase