title: Discovery and crystallography of bicyclic arylaminoazines as potent inhibitors of HIV-1 reverse transcriptase.
abstract: Non-nucleoside inhibitors of HIV-1 reverse transcriptase (HIV-RT) are reported that incorporate a 7-indolizinylamino or 2-naphthylamino substituent on a pyrimidine or 1,3,5-triazine core. The most potent compounds show below 10 nanomolar activity towards wild-type HIV-1 and variants bearing Tyr181Cys and Lys103Asn/Tyr181Cys resistance mutations. The compounds also feature good aqueous solubility. Crystal structures for two complexes enhance the analysis of the structure-activity data.
authors.affiliation: Department of Chemistry, Yale University, New Haven, CT 06520-8107, USA.
authors.forename: Won-Gil
authors.initials: WG
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520-8066, USA.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Frey
authors.affiliation: Department of Chemistry, Yale University, New Haven, CT 06520-8107, USA.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Gallardo-Macias
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520-8066, USA.
authors.forename: Krasimir A
authors.initials: KA
authors.lastname: Spasov
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520-8066, USA.
authors.forename: Albert H
authors.initials: AH
authors.lastname: Chan
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520-8066, USA. Electronic address: karen.anderson@yale.edu.
authors.forename: Karen S
authors.initials: KS
authors.lastname: Anderson
authors.affiliation: Department of Chemistry, Yale University, New Haven, CT 06520-8107, USA. Electronic address: william.jorgensen@yale.edu.
authors.forename: William L
authors.initials: WL
authors.lastname: Jorgensen
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D053961:Azabicyclo Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006678:HIV / Q000187:drug effects*; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D012995:Solubility; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D019380:Anti-HIV Agents; D053961:Azabicyclo Compounds; D001643:Bridged Bicyclo Compounds; D018894:Reverse Transcriptase Inhibitors; D014227:Triazines; D054303:HIV Reverse Transcriptase
keywords: Drug solubility; HIV-1 reverse transcriptase; NNRTI; Protein crystallography; Structure-based drug design