Structure-activity relationship studies of novel benzophenones leading to the discovery of a potent, next generation HIV nonnucleoside reverse transcriptase inhibitor

Journal of Medicinal Chemistry

Volumn 49, Issue 2, 2006, Pages 727-739

  Romines, Karen R ^a   Freeman, George A ^a   Schaller, Lee T ^a   Cowan, Jill R ^a   Gonzales, Steve S ^a   Tidwell, Jeffrey H ^a   Andrews III, Clarence W ^a   Stammers, David K ^b   Hazen, Richard J ^a   Ferris, Robert G ^a   Short, Steven A ^a   Chan, Joseph H ^a   Boone, Lawrence R ^a  

^a GLAXOSMITHKLINE   (United States)

^b UNIVERSITY OF OXFORD   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

BENZOPHENONE; EFAVIRENZ; GW 678248; NEVIRAPINE; RNA DIRECTED DNA POLYMERASE INHIBITOR;

ANTIVIRAL ACTIVITY; ARTICLE; DRUG CLEARANCE; DRUG EFFICACY; DRUG POTENCY; DRUG SAFETY; HIGH THROUGHPUT SCREENING; HIGHLY ACTIVE ANTIRETROVIRAL THERAPY; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS INFECTED PATIENT; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; IC 50; STRAIN DIFFERENCE; STRUCTURE ACTIVITY RELATION; VIRUS RESISTANCE;

ANIMALS; ANTI-HIV AGENTS; BENZOPHENONES; CELL LINE; DOGS; DRUG RESISTANCE, VIRAL; HIV-1; HIV-1 REVERSE TRANSCRIPTASE; HUMANS; MACACA FASCICULARIS; MALE; MUTATION; NEVIRAPINE; NITRILES; OXAZINES; REVERSE TRANSCRIPTASE INHIBITORS; STRUCTURE-ACTIVITY RELATIONSHIP; SULFONAMIDES;

EID: 31544435514     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm050670l     Document Type: Article

References (16)

1. Staszewski, S.; Morales-Ramirez, J.; Tashima, K. T.; Rachlis, A.; Skiest, D.; Stanford, J.; Stryker, R.; Johnson, P.; Labriola, D. F.; Farina, D.; Manion, D. J.; Ruiz, N. M. Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults. N. Engl. J. Med. 1999, 341, 1865-1873.
2. Zhang, Z.; Hamatake, R.; Hong, Z. Clinical utility of current NNRTIs and perspectives of new agents in this class under development. Antiviral. Chem. Chemother. 2004, 15, 121-134.
3. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Published by the US Department of Health and Human Services. Oct 29, 2004. Available at http://AIDSinfo.nih.gov.
4. Grant, R. M.; Hecht, F. M.; Warmerdam, M.; Liu, L.; Liegler, T.; Petropoulos, C. J.; Hellmann, N. S.; Chesney, M.; Busch, M. P.; Kahn, J. O. Time trends in primaiy HIV-1 drug resistance among recently infected persons. JAMA 2002, 288, 181-188.
5. Ross, L. L.; Lim, M. L.; Liao, Q.; Wine, B.; Rodriguez, A. E.; Weinberg, W.; Shaefer, M. Prevalence of antiretroviral drug resistance and resistance mutations in antiretroviral therapy (ART) naïve HIV infected individuals from 44 cities during 2003. Presented at the 44th Interscience Conference on Antimicrobial Agents and Chemotherapy Meeting, Oct. 30 - Nov. 2, 2004, Washington, DC, Abstract H-173.
6. Wyatt, P. G.; Bethell, R. C.; Cammack, N.; Charon, D.; Dodic, N.; Dumaitre, B.; Evans, D. N.; Green, D. V. S.; Hopewell, P. L.; Humber, D. C.; Lamont, R. B.; Orr, D. C.; Plested, S. J.; Ryan, D. M.; Sollis, S. L.; Storer, R.; Weingarten, G. G. Benzophenone derivatives: A novel series of potent and selective inhibitors of human immunodeficiency virus type I reverse transcriptase. J. Med. Chem. 1995, 38, 1657-1665.
7. Chan, J. H.; Freeman, G. A.; Tidwell, J. H.; Romines, K. R.; Schaller, LT.; Cowan, J. R.; Gonzales, S. S.; Lowell, Q. S.; Andrews, C. W.; Reynolds, D. J.; St. Clair, M.; Hazen, R. J.; Ferris, R. G.; Creech, K. L.; Roberts, G. B.; Short, S. A.; Weaver, K.; Koszalka, G. W.; Boone, L. R. Novel benzophenones as nonnucleoside reverse transcriptase inhibitors of HIV-1. J. Med. Chem. 2004, 47, 1175-1182.
8. (a) Stammers, D. K.; Stuart, D. I.; Ren, J.; Chamberlain, P. P.; Weaver, K.; Short, S.; Andrews, C.; Romines, K.; Boone, L.; Schaller, L.; Freeman, A.; Chan, J. Structural studies of benzophenone/HIV-1 RT complexes: Insights into the potency of the next generation NNRTIs against wt and mutant HIV-1. Presented at the XIII International HIV Drug Resistance Workshop, June 8-12, 2004, Canary Islands, Spain, Poster 30.
9. (b) Stammers, D. K., et al., unpublished results.
10. Structure-activity relationships in this manuscript were determined using HIV antiviral assays. These antiviral assays have been shown to correlate well with enzyme inhibition in biochemical assays (ref 7, footnote 10).
11. Ferris, R.; Hazen, R.; Roberts, G.; St. Clair, M.; Chan, J.; Romines, K.; Freeman, G.; Tidwell, J.; Schaller, L.; Cowan, J.; Short, S.; Weaver, K.; Selleseth, D.; Monirl, K.; Boone, L. Antiviral activity of GW678248, a novel benzophenone nonnucleoside reverse transcriptase inhibitor. Antimicrob. Agents Chemother. 2005, 49, 4046-4051.
12. 2-Bromo-1-methoxy-4-(trifluoromethyl)benzene was obtained by O-methylation of triflouro-p-cresol using methyl idodide and potassium carbonate in acetone, followed by bromination using bromine and sodium acetate in acetic acid.
13. The chloro starting material 43 was not commercially available, so we prepared it in two steps from 6-methyl-2-pyridineamine. The 3-nitro group was installed using sulfuric and fuming nitric acids, and the amine was converted to a chloro group using trimethylsilyl chloride and tert-butyl nitrite.
14. Kamm, O. β-Phenylhydroxylamine. Organic Syntheses Collective Volume I; Blatt, A. H., Ed.; John Wiley & Sons: New York, 1932; pp 445-447.
15. Kimpton, J.; Emerman, M. Detection of Replication-competent and Pseudotyped Human Immunodeficiency Virus with a Sensitive Cell Line on the Basis of Activation of an Integrated β-galactosidase Gene. J. Virol. 1992, 66, 2232-2239.
16. Fisher, A. G.; Collati, E.; Ratner, L.; Gallo, R. C.; Wong-Stall, F. A molecular clone of HTLV-III with biological activity. Nature 1985, 316, 262-265.