Novel nonnucleoside inhibitors of HIV-1 reverse transcriptase. 7. 8-Arylethyldipyridodiazepinones as potent broad-spectrum inhibitors of wild-type and mutant enzymes

J M Klunder; M Hoermann; C L Cywin; E David; J R Brickwood; R Schwartz; K J Barringer; D Pauletti; C K Shih; D A Erickson; C L Sorge; D P Joseph; S E Hattox; J Adams; P M Grob

doi:10.1021/jm9707028

Novel nonnucleoside inhibitors of HIV-1 reverse transcriptase. 7. 8-Arylethyldipyridodiazepinones as potent broad-spectrum inhibitors of wild-type and mutant enzymes

J Med Chem. 1998 Jul 30;41(16):2960-71. doi: 10.1021/jm9707028.

Authors

J M Klunder¹, M Hoermann, C L Cywin, E David, J R Brickwood, R Schwartz, K J Barringer, D Pauletti, C K Shih, D A Erickson, C L Sorge, D P Joseph, S E Hattox, J Adams, P M Grob

Affiliation

¹ Departments of Medicinal Chemistry, Inflammatory Diseases, and Drug Metabolism and Pharmacokinetics, Research and Development Center, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, P.O. Box 368, Ridgefield, Connecticut 06877, USA.

PMID: 9685235
DOI: 10.1021/jm9707028

Abstract

Like other nonnucleoside inhibitors of HIV-1 reverse transcriptase, the dipyridodiazepinone nevirapine (Viramune, 1) selects for drug resistant variants of HIV-1, both in cell culture and in patients. In particular, the mutation of residue 181 from tyrosine to cysteine (Y181C) is associated with resistance to most reported nonnucleoside inhibitors. Introduction of an arylethyl substituent at the 8-position of the tricyclic dipyridodiazepinone skeleton confers enhanced potency against Y181C RT. Several analogues of this series display good broad spectrum potency against a panel of mutant enzymes.

MeSH terms

Amino Acid Substitution
Antiviral Agents / chemical synthesis*
Antiviral Agents / chemistry
Antiviral Agents / pharmacology
Azepines / chemical synthesis*
Azepines / chemistry
Azepines / pharmacology
Cell Line, Transformed
Drug Resistance, Microbial
HIV Reverse Transcriptase / antagonists & inhibitors*
HIV Reverse Transcriptase / genetics
HIV-1 / drug effects
HIV-1 / enzymology
HIV-1 / genetics
Humans
In Vitro Techniques
Microsomes, Liver / drug effects
Microsomes, Liver / metabolism
Mutation*
Nevirapine / chemistry
Nevirapine / pharmacology
Pyridines / chemical synthesis*
Pyridines / chemistry
Pyridines / pharmacology
Reverse Transcriptase Inhibitors / chemical synthesis*
Reverse Transcriptase Inhibitors / chemistry
Reverse Transcriptase Inhibitors / pharmacology
Structure-Activity Relationship

Substances

Antiviral Agents
Azepines
Pyridines
Reverse Transcriptase Inhibitors
Nevirapine
HIV Reverse Transcriptase