title: 10-Hydroxy-7,8-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-diones: potent, orally bioavailable HIV-1 integrase strand-transfer inhibitors with activity against integrase mutants.
abstract: A series of 10-hydroxy-7,8-dihydropyrazino[1',2':1,5]pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-diones was synthesized and tested for their inhibition of HIV-1 replication in cell culture. Structure-activity studies indicated that high antiviral potency against wild-type virus as well as viruses containing integrase mutations that confer resistance to three different structural classes of integrase inhibitors could be achieved by incorporation of small aliphatic groups at certain positions on the core template. An optimal compound from this study, 16, inhibits integrase strand-transfer activity with an IC(50) value of 10 nM, inhibits HIV-1 replication in cell culture with an IC(95) value of 35 nM in the presence of 50% normal human serum, and displays modest pharmacokinetic properties in rats (i.v. t(1/2)=5.3 h, F=17%).
authors.affiliation: Department of Medicinal Chemistry, WP14-3, Merck Research Laboratories, West Point, PA 19486, USA. cathy_wiscount@merck.com
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Wiscount
authors.forename: Peter D
authors.initials: PD
authors.lastname: Williams
authors.forename: Lekhanh O
authors.initials: LO
authors.lastname: Tran
authors.forename: Mark W
authors.initials: MW
authors.lastname: Embrey
authors.forename: Thorsten E
authors.initials: TE
authors.lastname: Fisher
authors.forename: Vanessa
authors.initials: V
authors.lastname: Sherman
authors.forename: Carl F
authors.initials: CF
authors.lastname: Homnick
authors.forename: D
authors.initials: D
authors.lastname: Donnette Staas
authors.forename: Terry A
authors.initials: TA
authors.lastname: Lyle
authors.forename: John S
authors.initials: JS
authors.lastname: Wai
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Vacca
authors.forename: ZiQiang
authors.initials: Z
authors.lastname: Wang
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: Michael D
authors.initials: MD
authors.lastname: Miller
authors.forename: Daria J
authors.initials: DJ
authors.lastname: Hazuda
authors.forename: Alysha M
authors.initials: AM
authors.lastname: Day
authors.forename: Lori J
authors.initials: LJ
authors.lastname: Gabryelski
authors.forename: Linda T
authors.initials: LT
authors.lastname: Ecto
authors.forename: William A
authors.initials: WA
authors.lastname: Schleif
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: DiStefano
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Kochansky
authors.forename: M Reza
authors.initials: MR
authors.lastname: Anari
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D019427:HIV Integrase / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D019426:Integrases / Q000235:genetics*; D008956:Models, Chemical; D009154:Mutation; D051381:Rats; D013329:Structure-Activity Relationship; D014779:Virus Replication
chemical_list: D000998:Antiviral Agents; D019427:HIV Integrase; D019426:Integrases