Synthesis and evaluation of C2-carbon-linked heterocyclic-5-hydroxy-6-oxo-dihydropyrimidine-4-carboxamides as HIV-1 integrase inhibitors

B Narasimhulu Naidu; Margaret E Sorenson; Manoj Patel; Yasutsugu Ueda; Jacques Banville; Francis Beaulieu; Sagarika Bollini; Ira B Dicker; Helen Higley; Zeyu Lin; Lori Pajor; Dawn D Parker; Brian J Terry; Ming Zheng; Alain Martel; Nicholas A Meanwell; Mark Krystal; Michael A Walker

doi:10.1016/j.bmcl.2014.11.060

Synthesis and evaluation of C2-carbon-linked heterocyclic-5-hydroxy-6-oxo-dihydropyrimidine-4-carboxamides as HIV-1 integrase inhibitors

Bioorg Med Chem Lett. 2015 Feb 1;25(3):717-20. doi: 10.1016/j.bmcl.2014.11.060. Epub 2014 Nov 27.

Authors

B Narasimhulu Naidu¹, Margaret E Sorenson², Manoj Patel², Yasutsugu Ueda², Jacques Banville², Francis Beaulieu², Sagarika Bollini³, Ira B Dicker³, Helen Higley³, Zeyu Lin³, Lori Pajor⁴, Dawn D Parker⁴, Brian J Terry³, Ming Zheng⁴, Alain Martel², Nicholas A Meanwell², Mark Krystal³, Michael A Walker²

Affiliations

¹ Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA. Electronic address: b.narasimhulunaidu@bms.com.
² Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
³ Department of Virology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.
⁴ Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.

PMID: 25529736
DOI: 10.1016/j.bmcl.2014.11.060

Abstract

Integration of viral DNA into the host cell genome is an obligatory process for successful replication of HIV-1. Integrase catalyzes the insertion of viral DNA into the target DNA and is a validated target for drug discovery. Herein, we report the synthesis, antiviral activity and pharmacokinetic profiles of several C2-carbon-linked heterocyclic pyrimidinone-4-carboxamides that inhibit the strand transfer step of the integration process.

Keywords: HIV-1; Inhibitor; Integrase; Pyrimidine-4-carboxamide; Strand transfer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amides / chemical synthesis
Amides / chemistry*
Amides / pharmacokinetics
Animals
HIV Integrase / chemistry*
HIV Integrase / metabolism
HIV Integrase Inhibitors / chemical synthesis*
HIV Integrase Inhibitors / chemistry
HIV Integrase Inhibitors / pharmacokinetics
HIV-1 / drug effects
HIV-1 / enzymology*
Half-Life
Heterocyclic Compounds / chemistry
Humans
Male
Pyrimidines / chemistry
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship

Substances

Amides
HIV Integrase Inhibitors
Heterocyclic Compounds
Pyrimidines
HIV Integrase
pyrimidine
p31 integrase protein, Human immunodeficiency virus 1