Design, synthesis and SAR study of bridged tricyclic pyrimidinone carboxamides as HIV-1 integrase inhibitors

Manoj Patel; B Narasimhulu Naidu; Ira Dicker; Helen Higley; Zeyu Lin; Brian Terry; Tricia Protack; Mark Krystal; Susan Jenkins; Dawn Parker; Chiradeep Panja; Richard Rampulla; Arvind Mathur; Nicholas A Meanwell; Michael A Walker

doi:10.1016/j.bmc.2020.115541

Design, synthesis and SAR study of bridged tricyclic pyrimidinone carboxamides as HIV-1 integrase inhibitors

Bioorg Med Chem. 2020 Jul 1;28(13):115541. doi: 10.1016/j.bmc.2020.115541. Epub 2020 May 4.

Authors

Affiliations

¹ Departments of Discovery Chemistry and Molecular Technologies, 5 Research Parkway, Wallingford, CT 06492, USA; ViiV Healthcare, 36 East Industrial Parkway, Branford, CT 06405, USA. Electronic address: manoj.m.patel@viivhealthcare.com.
² Departments of Discovery Chemistry and Molecular Technologies, 5 Research Parkway, Wallingford, CT 06492, USA; ViiV Healthcare, 36 East Industrial Parkway, Branford, CT 06405, USA.
³ Virology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA; ViiV Healthcare, 36 East Industrial Parkway, Branford, CT 06405, USA.
⁴ Virology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
⁵ Biocon-Bristol-Myers Squibb Research Center, Plot 2 & 3, Bommasandra Industrial Estate - Phase-IV, Bommasandra-Jigani Link Road, Bengaluru, Karnataka 560099, India.
⁶ Department of Discovery Chemistry Synthesis, Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543-4000, USA.
⁷ Departments of Discovery Chemistry and Molecular Technologies, 5 Research Parkway, Wallingford, CT 06492, USA.
⁸ Departments of Discovery Chemistry and Molecular Technologies, 5 Research Parkway, Wallingford, CT 06492, USA; Assembly Biosciences, Inc. 331 Oyster Point Blvd, San Francisco, CA 94080, USA.

PMID: 32389483
DOI: 10.1016/j.bmc.2020.115541

Abstract

The design, synthesis and structure-activity relationships associated with a series of bridged tricyclic pyrimidinone carboxamides as potent inhibitors of HIV-1 integrase strand transfer are described. Structural modifications to these molecules were made in order to examine the effect on potency towards wild-type and clinically-relevant resistant viruses. The [3.2.2]-bridged tricyclic system was identified as an advantageous chemotype, with representatives exhibiting excellent antiviral activity against both wild-type viruses and the G140S/Q148H resistant virus that arises in response to therapy with raltegravir and elvitegravir.

Keywords: Bridged tricyclic pyrimidinone; HIV; HIV Integrase; Integrase inhibitor; Strand transfer inhibitor.

MeSH terms

Antiviral Agents / chemical synthesis*
Antiviral Agents / pharmacology
Drug Resistance, Viral / drug effects
Drug Therapy, Combination
HIV Infections / drug therapy*
HIV Integrase / metabolism*
HIV Integrase Inhibitors / chemical synthesis*
HIV Integrase Inhibitors / pharmacology
HIV-1 / drug effects
Humans
Imidazoles / chemical synthesis*
Imidazoles / pharmacology
Mutation
Pyrrolidinones / chemistry*
Quinolones / pharmacology
Raltegravir Potassium / pharmacology
Structure-Activity Relationship

Substances

Antiviral Agents
HIV Integrase Inhibitors
Imidazoles
Pyrrolidinones
Quinolones
Raltegravir Potassium
elvitegravir
HIV Integrase