Synthesis of 5-(1-H or 1-alkyl-5-oxopyrrolidin-3-yl)-8-hydroxy-[1,6]-naphthyridine-7-carboxamide inhibitors of HIV-1 integrase

Bioorganic and Medicinal Chemistry Letters

Volumn 18, Issue 19, 2008, Pages 5307-5310

  Melamed, Jeffrey Y ^a   Egbertson, Melissa S ^a   Varga, Sandor ^a   Vacca, Joseph P ^a   Moyer, Greg ^a   Gabryelski, Lori ^a   Felock, Peter J ^a   Stillmock, Kara A ^a   Witmer, Marc V ^a   Schleif, William ^a   Hazuda, Daria J ^a   Leonard, Yvonne ^a   Jin, Lixia ^a   Ellis, Joan D ^a   Young, Steven D ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

1,6 Naphthyridine; Antiviral; Butenolide; HIV; Integrase; Pyrrolidinone synthesis

Indexed keywords

2 PYRROLIDONE DERIVATIVE; AMIDE; BUTENOLIDE; HYDROXYL GROUP; INTEGRASE; INTEGRASE INHIBITOR; N (4 FLUOROBENZYL) 8 HYDROXY 1,6 NAPHTHYRIDINE 7 CARBOXAMIDE; NAPHTHYRIDINE DERIVATIVE; NITROGEN; PYRROLIDINE DERIVATIVE; UNCLASSIFIED DRUG; VIRUS DNA;

ANIMAL EXPERIMENT; ANTIVIRAL ACTIVITY; ARTICLE; CONTROLLED STUDY; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG HALF LIFE; DRUG POTENCY; DRUG PROTEIN BINDING; DRUG SELECTIVITY; DRUG SYNTHESIS; ENZYME MECHANISM; HOST CELL; HUMAN IMMUNODEFICIENCY VIRUS 1; NONHUMAN; RAT; STEREOSPECIFICITY; STRUCTURE ACTIVITY RELATION; VIRUS GENOME; VIRUS REPLICATION;

ADMINISTRATION, ORAL; ANIMALS; ANTI-HIV AGENTS; HIV INTEGRASE; HIV INTEGRASE INHIBITORS; HIV-1; MOLECULAR STRUCTURE; NAPHTHYRIDINES; RATS; STRUCTURE-ACTIVITY RELATIONSHIP;

HUMAN IMMUNODEFICIENCY VIRUS 1;

EID: 52049086004     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2008.08.038     Document Type: Article

References (21)

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12. 4F (M+H): 380.1041, Found: 380.1050.
13. 3F (M+H): 424.1786, Found: 424.1781.
14. 6), δ 13.25 (1H, br s), 9.68 (1H, t, J = 6.4 Hz), 8.44 (1H, d, J = 7.3 Hz), 8.10 (1H, m), 7.95 (1H, s), 7.43 (2H, m), 7.19 (3H, m), 4.64 (2H, d, J = 6.5 Hz), 3.87 (3H, s), 3.68 (2H, s), 2.48 (3H, d, J = 4.5 Hz).
15. 3F (M+H): 393.1357, Found: 393.1357.
16. 6), δ 13.55.
17. Examples of the synthesis of various substituted 4-aryl-pyrrolidinones from the corresponding butenolides: {A figure is presented}.
18. Resolution of 9 by chiral HPLC provides optically pure (+) and (-) isomers which are equipotent in the enzyme and cellular assays.
19. Analytical HPLC/UV detection-based assay that measures the ability of a compound to bind with human plasma (primarily Albumin) in pH 7.4 buffer at room temperature. Each value is the result of the average of three determinations.
20. 4/NaOH) water layer. Log P = log (Octanol HPLC area)(Octanol dilution)/(Buffer HPLC area)(Buffer dilution).
21. Perlow D.S., Juo S., Moritz H.M., Wai J.S., and Egbertson M.S. Synth. Commun. 37 (2007) 1887