title: Pyrimidine thioethers: a novel class of HIV-1 reverse transcriptase inhibitors with activity against BHAP-resistant HIV.
abstract: A series of pyrimidine thioethers was synthesized and evaluated for inhibitory properties against wild-type HIV-1 reverse transcriptase (RT) and an RT carrying the resistance-conferring mutation P236L. Modifications of both the pyrimidine and the functionality attached through the thioether yielded several analogues, which demonstrated activity against both enzyme types, with IC50 values as low as 190 nM against wild-type and 66 nM against P236L RT. Evaluation of a select number of pyrimidine thioethers in cell culture showed that these compounds have excellent activity against HIV-1IIIB-WT and retain good activity against a laboratory-derived HIV-1MF delavirdine-resistant variant.
authors.affiliation: Departments of Medicinal Chemistry, Discovery Technology, and Infectious Diseases, Pharmacia & Upjohn, Kalamazoo, Michigan 49001-0199, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Nugent
authors.forename: S T
authors.initials: ST
authors.lastname: Schlachter
authors.forename: M J
authors.initials: MJ
authors.lastname: Murphy
authors.forename: G J
authors.initials: GJ
authors.lastname: Cleek
authors.forename: T J
authors.initials: TJ
authors.lastname: Poel
authors.forename: D G
authors.initials: DG
authors.lastname: Wishka
authors.forename: D R
authors.initials: DR
authors.lastname: Graber
authors.forename: Y
authors.initials: Y
authors.lastname: Yagi
authors.forename: B J
authors.initials: BJ
authors.lastname: Keiser
authors.forename: R A
authors.initials: RA
authors.lastname: Olmsted
authors.forename: L A
authors.initials: LA
authors.lastname: Kopta
authors.forename: S M
authors.initials: SM
authors.lastname: Swaney
authors.forename: S M
authors.initials: SM
authors.lastname: Poppe
authors.forename: J
authors.initials: J
authors.lastname: Morris
authors.forename: W G
authors.initials: WG
authors.lastname: Tarpley
authors.forename: R C
authors.initials: RC
authors.lastname: Thomas
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D020008:Delavirdine / Q000494:pharmacology*; D004352:Drug Resistance, Microbial; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology; D007930:Leucine / Q000235:genetics; D051379:Mice; D011392:Proline / Q000235:genetics; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; D013440:Sulfides; D011392:Proline; D020008:Delavirdine; D054303:HIV Reverse Transcriptase; D007930:Leucine