title: A series of 5-(5,6)-dihydrouracil substituted 8-hydroxy-[1,6]naphthyridine-7-carboxylic acid 4-fluorobenzylamide inhibitors of HIV-1 integrase and viral replication in cells.
abstract: Introduction of a 5,6-dihydrouracil functionality in the 5-position of N-(4-fluorobenzyl)-8-hydroxy-[1,6]naphthyridine-7-carboxamide 1 led to a series of highly active HIV-1 integrase inhibitors. These compounds displayed low nanomolar activity in inhibiting both the strand transfer process of HIV-1 integrase and viral replication in cells. Compound 11 is a 150-fold more potent antiviral agent than 1, with a CIC(95) of 40 nM in the presence of human serum. It displays good pharmacokinetics when dosed in rats and dogs.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. mark_embrey@merck.com
authors.forename: Mark W
authors.initials: MW
authors.lastname: Embrey
authors.forename: John S
authors.initials: JS
authors.lastname: Wai
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Funk
authors.forename: Carl F
authors.initials: CF
authors.lastname: Homnick
authors.forename: Debbie S
authors.initials: DS
authors.lastname: Perlow
authors.forename: Steven D
authors.initials: SD
authors.lastname: Young
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Vacca
authors.forename: Daria J
authors.initials: DJ
authors.lastname: Hazuda
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Felock
authors.forename: Kara A
authors.initials: KA
authors.lastname: Stillmock
authors.forename: Marc V
authors.initials: MV
authors.lastname: Witmer
authors.forename: Gregory
authors.initials: G
authors.lastname: Moyer
authors.forename: William A
authors.initials: WA
authors.lastname: Schleif
authors.forename: Lori J
authors.initials: LJ
authors.lastname: Gabryelski
authors.forename: Lixia
authors.initials: L
authors.lastname: Jin
authors.forename: I-Wu
authors.initials: IW
authors.lastname: Chen
authors.forename: Joan D
authors.initials: JD
authors.lastname: Ellis
authors.forename: Bradley K
authors.initials: BK
authors.lastname: Wong
authors.forename: Jiunn H
authors.initials: JH
authors.lastname: Lin
authors.forename: Yvonne M
authors.initials: YM
authors.lastname: Leonard
authors.forename: Nancy N
authors.initials: NN
authors.lastname: Tsou
authors.forename: Linghang
authors.initials: L
authors.lastname: Zhuang
mesh_terms: D000818:Animals; D001593:Benzyl Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D018360:Crystallography, X-Ray; D019428:HIV Integrase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D009287:Naphthyridines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D014498:Uracil / Q000031:analogs & derivatives* / Q000737:chemistry; D014779:Virus Replication / Q000187:drug effects*
chemical_list: C505998:8-hydroxy-(1,6)naphthyridine-7-carboxylic acid 4-fluorobenzylamide; D001593:Benzyl Compounds; D019428:HIV Integrase Inhibitors; D009287:Naphthyridines; C007419:dihydrouracil; D014498:Uracil