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.
Brian A Johns  1 ,  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
Affiliations
  • 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.