title: Bicyclic hydroxy-1H-pyrrolopyridine-trione containing HIV-1 integrase inhibitors.
abstract: HIV-1 integrase (IN) is a validated therapeutic target for the treatment of AIDS. However, the emergence of resistance to raltegravir, the sole marketed FDA-approved IN inhibitor, emphasizes the need to develop second-generation inhibitors that retain efficacy against clinically relevant IN mutants. We report herein bicyclic hydroxy-1H-pyrrolopyridine-triones as a new family of HIV-1 integrase inhibitors that were efficiently prepared using a key 'Pummerer cyclization deprotonation cycloaddition' cascade of imidosulfoxides. In in vitro HIV-1 integrase assays, the analogs showed low micromolar inhibitory potencies with selectivity for strand transfer reactions as compared with 3'-processing inhibition. A representative inhibitor (5e) retained most of its inhibitory potency against the three major raltegravir-resistant IN mutant enzymes, G140S/Q148H, Y143R, and N155H. In antiviral assays employing viral vectors coding these IN mutants, compound 5e was approximately 200- and 20-fold less affected than raltegravir against the G140S/Q148H and Y143R mutations, respectively. Against the N155H mutation, 5e was approximately 10-fold less affected than raltegravir. Thus, our new compounds represent a novel structural class that may be further developed to overcome resistance to raltegravir, particularly in the case of the G140S/Q148H mutations.
authors: Chemical Biology Laboratory, Molecular Discovery Program, Center for Cancer Research, National Cancer Institute-Frederick, National Institutes of Health, Frederick, MD 21702, USA.
authors: Xue Zhi
authors: XZ
authors: Zhao
authors: Kasthuraiah
authors: K
authors: Maddali
authors: Mathieu
authors: M
authors: Metifiot
authors: Steven J
authors: SJ
authors: Smith
authors: B Christie
authors: BC
authors: Vu
authors: Christophe
authors: C
authors: Marchand
authors: Stephen H
authors: SH
authors: Hughes
authors: Yves
authors: Y
authors: Pommier
authors: Terrence R
authors: TR
authors: Burke
mesh_terms: D019943:Amino Acid Substitution; D001665:Binding Sites; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D003198:Computer Simulation; D024882:Drug Resistance, Viral / Q000187:drug effects; D019427:HIV Integrase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007094:Imides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D009154:Mutation; D011725:Pyridines / Q000737:chemistry*; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D000068898:Raltegravir Potassium
chemical_list: D001643:Bridged Bicyclo Compounds; D019428:HIV Integrase Inhibitors; D007094:Imides; D011725:Pyridines; D011728:Pyridones; D011760:Pyrrolidinones; C571718:methyl 3-(2-(3-chloro-4-fluorobenzyl)-7-hydroxy-5-isopropyl-1,3,6-trioxo-2,3,5,6-tetrahydro-1H-pyrrolo(3,4-c)pyridin-4-yl)propanoate; D000068898:Raltegravir Potassium; D019427:HIV Integrase; C023666:pyridine; C514801:p31 integrase protein, Human immunodeficiency virus 1