Naphthyridinone (NTD) integrase inhibitors: N1 protio and methyl combination substituent effects with C3 amide groups

Brian A Johns; Takashi Kawasuji; Jason G Weatherhead; Eric E Boros; James B Thompson; Cecilia S Koble; Edward P Garvey; Scott A Foster; Jerry L Jeffrey; Tamio Fujiwara

doi:10.1016/j.bmcl.2012.11.071

Naphthyridinone (NTD) integrase inhibitors: N1 protio and methyl combination substituent effects with C3 amide groups

Bioorg Med Chem Lett. 2013 Jan 15;23(2):422-5. doi: 10.1016/j.bmcl.2012.11.071. Epub 2012 Dec 3.

Authors

Brian A Johns¹, Takashi Kawasuji, Jason G Weatherhead, Eric E Boros, James B Thompson, Cecilia S Koble, Edward P Garvey, Scott A Foster, Jerry L Jeffrey, Tamio Fujiwara

Affiliation

¹ GlaxoSmithKline Research & Development, Infectious Diseases Therapy Area Unit, Five Moore Drive, Research Triangle Park, NC 27709, USA. [email protected]

PMID: 23245515
DOI: 10.1016/j.bmcl.2012.11.071

Abstract

Substituent effects of a series of N1 protio and methyl naphthyridinone HIV-1 integrase strand-transfer inhibitors has been explored. The effects of combinations of the N1 substituent and C3 amide groups was extensively studied to compare enzyme inhibition, antiviral activity and protein binding effects on potency. The impact of substitution on ligand efficiency was considered and several compounds were advanced into in vivo pharmacokinetic studies ultimately leading to the clinical candidate GSK364735.

MeSH terms

Amides / chemistry*
Biological Assay
Enzyme Activation / drug effects
HIV Integrase Inhibitors / chemical synthesis
HIV Integrase Inhibitors / chemistry
HIV Integrase Inhibitors / pharmacology
Humans
Inhibitory Concentration 50
Molecular Structure
Naphthyridines / chemistry*
Naphthyridines / pharmacology
Structure-Activity Relationship

Substances

Amides
HIV Integrase Inhibitors
Naphthyridines
GSK364735