Synthesis of 5-(1-H or 1-alkyl-5-oxopyrrolidin-3-yl)-8-hydroxy-[1,6]-naphthyridine-7-carboxamide inhibitors of HIV-1 integrase.
HIV-1 integrase catalyzes the insertion of viral DNA into the genome of the host cell. Integrase inhibitor N-(4-fluorobenzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamide selectively inhibits the strand transfer process of integration. 4-Substituted pyrrolidinones possessing various groups on the pyrrolidinone nitrogen were introduced at the 5-position of the naphthyridine scaffold. These analogs exhibit excellent activity against viral replication in a cell-based assay. The preparation of these compounds was enabled by a three-step, two-pot reaction sequence from a common butenolide intermediate.
Melamed
Jeffrey Y
JY
Department of Medicinal Chemistry, Merck Research Laboratories, 770 Sumneytown Pike, PO Box 4, West Point, PA 19486, USA. jeffrey_melamed@merck.com
Egbertson
Melissa S
MS
Varga
Sandor
S
Vacca
Joseph P
JP
Moyer
Greg
G
Gabryelski
Lori
L
Felock
Peter J
PJ
Stillmock
Kara A
KA
Witmer
Marc V
MV
Schleif
William
W
Hazuda
Daria J
DJ
Leonard
Yvonne
Y
Jin
Lixia
L
Ellis
Joan D
JD
Young
Steven D
SD
D000284:Administration, Oral; D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D019427:HIV Integrase / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects*; D015394:Molecular Structure; D009287:Naphthyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
D019380:Anti-HIV Agents; D019428:HIV Integrase Inhibitors; C532528:N-(4-fluorobenzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamide; D009287:Naphthyridines; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1