Design and synthesis of substituted 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamides, novel HIV-1 integrase inhibitors.
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.
Langford
H Marie
HM
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. hmarie_langford@merck.com
Williams
Peter D
PD
Homnick
Carl F
CF
Vacca
Joseph P
JP
Felock
Peter J
PJ
Stillmock
Kara A
KA
Witmer
Marc V
MV
Hazuda
Daria J
DJ
Gabryelski
Lori J
LJ
Schleif
William A
WA
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
D019428:HIV Integrase Inhibitors; D011719:Pyrazines; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1