title: Design and synthesis of substituted 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamides, novel HIV-1 integrase inhibitors.
abstract: A series of 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamides was synthesized and tested for their inhibition of HIV-1 integrase catalytic activity and HIV-1 replication in cells. Structure-activity studies around lead compound 5 indicated that a coplanar relationship of metal-binding heteroatoms provides optimal binding to the integrase active site. Identification of potency-enhancing substituents and adjustments in lipophilicity provided 17b which inhibits integrase-catalyzed strand transfer with an IC(50) value of 74 nM and inhibits HIV-1 replication in cell culture in the presence of 50% normal human serum with an IC(95) value of 63 nM.
authors: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. hmarie_langford@merck.com
authors: H Marie
authors: HM
authors: Langford
authors: Peter D
authors: PD
authors: Williams
authors: Carl F
authors: CF
authors: Homnick
authors: Joseph P
authors: JP
authors: Vacca
authors: Peter J
authors: PJ
authors: Felock
authors: Kara A
authors: KA
authors: Stillmock
authors: Marc V
authors: MV
authors: Witmer
authors: Daria J
authors: DJ
authors: Hazuda
authors: Lori J
authors: LJ
authors: Gabryelski
authors: William A
authors: WA
authors: Schleif
mesh_terms: D002384:Catalysis; D002460:Cell Line; D019427:HIV Integrase / Q000187:drug effects* / Q000378:metabolism; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015497:HIV-1 / Q000201:enzymology / Q000502:physiology; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019428:HIV Integrase Inhibitors; D011719:Pyrazines; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1