title: Synthesis of 5-(1-H or 1-alkyl-5-oxopyrrolidin-3-yl)-8-hydroxy-[1,6]-naphthyridine-7-carboxamide inhibitors of HIV-1 integrase.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, 770 Sumneytown Pike, PO Box 4, West Point, PA 19486, USA. jeffrey_melamed@merck.com
authors.forename: Jeffrey Y
authors.initials: JY
authors.lastname: Melamed
authors.forename: Melissa S
authors.initials: MS
authors.lastname: Egbertson
authors.forename: Sandor
authors.initials: S
authors.lastname: Varga
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Vacca
authors.forename: Greg
authors.initials: G
authors.lastname: Moyer
authors.forename: Lori
authors.initials: L
authors.lastname: Gabryelski
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: William
authors.initials: W
authors.lastname: Schleif
authors.forename: Daria J
authors.initials: DJ
authors.lastname: Hazuda
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Leonard
authors.forename: Lixia
authors.initials: L
authors.lastname: Jin
authors.forename: Joan D
authors.initials: JD
authors.lastname: Ellis
authors.forename: Steven D
authors.initials: SD
authors.lastname: Young
mesh_terms: 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
chemical_list: 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