Tricyclic HIV integrase inhibitors V. SAR studies on the benzyl moiety

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 8, 2009, Pages 2263-2265

  Jin, Haolun ^a   Metobo, Sammy ^a   Jabri, Salman ^a   Mish, Michael ^a   Lansdown, Rachael ^a   Chen, Xiaowu ^a   Tsiang, Manuel ^a   Wright, Matthew ^a   Kim, Choung U ^a  

^a GILEAD SCIENCES   (United States)

Author keywords

AIDS; Benzyl moiety; HIV; Integrase inhibitor; Tricyclic

Indexed keywords

3 CHLORO 4 FLUOROBENZYL BROMIDE; BENZYL DERIVATIVE; INTEGRASE INHIBITOR; RALTEGRAVIR; TRICYCLIC AROMATIC COMPOUND; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ARTICLE; DOG; DRUG CLEARANCE; DRUG HALF LIFE; DRUG POTENCY; DRUG STRUCTURE; HUMAN; HUMAN CELL; HUMAN IMMUNODEFICIENCY VIRUS; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; NONHUMAN; RAT; STRUCTURE ACTIVITY RELATION; STRUCTURE ANALYSIS; VIRUS INHIBITION;

ANIMALS; ANTI-HIV AGENTS; BINDING, COMPETITIVE; BIOLOGICAL AVAILABILITY; CELL LINE; DOGS; FLUOROBENZENES; HIV INTEGRASE INHIBITORS; HIV-1; HUMANS; RATS; STRUCTURE-ACTIVITY RELATIONSHIP; TUMOR CELLS, CULTURED;

EID: 63149102745     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.02.092     Document Type: Article

References (11)

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8. Strand transfer assay modified from a previous report (Hazuda et al., Nucleic Acid Res. 1994, 22, 1121). Biotinylated donor DNA was bound to Reacti-Bind High Binding Capacity Streptavidin coated white plates. DIG-tagged target DNA with anti-DIG antibody-conjugated horse radish peroxidase detection was used.
9. 4 cells) were then added to each well containing the drug dilutions. The plates are incubated at 37 °C for 5 days. One hundred microlitres of CellTiter-Glo™ Reagent (catalog # G7571, Promega Biosciences, Inc., Madison, WI) were then added to each well. Cell lysis was allowed to complete by incubating at room temperature for 10 min. Chemiluminescence was then read. For the cytotoxicity assay, the protocol is identical to that of the antiviral assay, except that uninfected cells and a threefold serial dilution of drugs were used.
10. 50 resulting from the combined effect of both proteins (as in serum) can be calculated. The derivation of the appropriate equation for this calculation can be made through competitive binding assumptions.
11. For 3-Cl-4-F-benzyl bromide (8): DeGraw, J. I.; Cory, M.; Skinner, W. A.; Theisen, M. C.; Mitoma, C. J. Med Chem. 1967, 10, 64; For 5-Cl-2,4-F-benzyl bromide (9 and 10), 2-CONHMe-4-F benzyl analog () and 2-NHAc-4-F-benzyl analog (13): US2007/72831; For 3-Cl-2,4-F-benzyl bromide (11): WO2007/61670 example 68.