- 4-Benzyl and 4-benzoyl-3-dimethylaminopyridin-2(1H)-ones: In vitro evaluation of new C-3-amino-substituted and C-5,6-alkyl-substituted analogues against clinically important HIV mutant strains
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In a program to optimize the anti-HIV activity of the 4-benzyl and 4-benzoyl-3-dimethylaminopyridinones 9 and 10, lead compounds in a new class of highly potent non-nucleoside type inhibitors of HIV-1 reverse transcriptase, modification of the alkyl substitutents at the C-5 and C-6 positions on the pyridinone ring and of the substitutents on the C-3 amino group has been studied. Of the 17 new 5/6-modified analogues prepared, compounds 31b and 32b substituted at C-5 by an extended nonpolar chain containing an ether function and a C-6 methyl group and compound 35 bearing a C-5 ethyl/C-6 hydroxymethyl substituent pattern were selected on the basis of their in vitro activity against wild-type HIV and the three principle mutant strains, K103N, Y181C, and Y188L. When tested further, it was shown that these molecules, and in particular compound 35, are globally more active than 9, 10, and efavirenz against an additional eight single [L100I, K101E, V106A, E138K, V179E, G190A/S, and F227C] and four double HIV mutant strains [L100I + K103N, K101E + K103N, K103N + Y181C, and F227L + V106A], which are clinically relevant. Concerning modulation of the N-3 substituent, 36 new analogues were prepared. Of these, the N-methyl-N-(2-methoxyethyl)-substituted compounds 40, 42, and 62, as well as the doubly modified compounds 77a and 77b, were selected from the initial screen and were subsequently shown to be active at sub-micromolar concentrations (IC50's) against all the other mutant strains except K103N + Y181C and F227L + V106A. Two possible, but distinct, modes of binding of these analogues in RT were suggested from molecular modeling studies. The preferred mode of binding for compound 62, corresponding to the predicted "orientation 1", was revealed in the X-ray crystal structure of the compound 62-RT complex.
- Benjahad, Abdellah,Croisy, Martine,Monneret, Claude,Bisagni, Emile,Mabire, Dominique,Coupa, Sophie,Poncelet, Alain,Csoka, Imre,Guillemont, Jér?me,Meyer, Christophe,Andries, Koen,Pauwels, Rudi,De Béthune, Marie-Pierre,Himmel, Daniel M.,Das, Kalyan,Arnold, Eddy,Chi, Hung Nguyen,Grierson, David S.
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p. 1948 - 1964
(2007/10/03)
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- ANTIPRURITICS
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It is intended to provide antipruritics (drugs to control itching, antiitch agents and drugs to stop itching). It is found out that a compound having an agonistic activity to the cannabinoid receptor shows an antipruritics effect.
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Page/Page column 29
(2008/06/13)
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- PYRIDONE DERIVATIVE HAVING AFFINITY FOR CANNABINOID 2-TYPE RECEPTOR
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It was found that the compound having a binding activity to the cannabinoid type 2 receptor represented by the formula (I): wherein R' is a group represented by the formula: -Y1-Y2-Y3Ra wherein Y1 is single bond or the like; Y2 is -C(=O)-NH- or the like; Y3 is optionally substituted aryl or the like; R2 is hydrogen or the like; R3 is alkyl or the like; R4 is alkyl or the like; R5 is optionally substituted alkyl or the like; or R3 and R4 taken together with the adjacent atom form cyclic group or the like.
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- Metallation in connection with cross-coupling reactions. Coupling of hindered aryls for the synthesis of 4-phenylpyridines as part of Streptonigrin and Lavendamycin analogues
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The synthesis of the C-D ring system of Streptonigrin and Lavendamycln alkaloid analogues by cross-coupling under Suzuki's conditions has been studied. Steric hindrance is the main problem. It has been solved either by using strong bases or working in a sealed tube under pressure.
- Godard,Rocca,Pomel,Thomas-Dit-Dumont,Rovera,Thaburet,Marsais,Queguiner
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- Synthesis and evaluation of 2-pyridinone derivatives as specific HIV-1 reverse transcriptase inhibitors. 3. Pyridyl and phenyl analogs of 3- aminopyridin-2(1H)-one
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In an ongoing effort to develop novel nonnucleoside, specific human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) inhibitors, a series of 3-[(pyridylmethyl)amino]- and 3-[(phenylmethyl)amino]-2- pyridinone derivatives was synthesized an
- Wai,Williams,Bamberger,Fisher,Hoffman,Hudcosky,MacTough,Rooney,Saari,Thomas,Goldman,O'Brien,Emini,Nunberg,Quintero,Schleif,Anderson
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p. 249 - 255
(2007/10/02)
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- A New Approach to the Synthesis Of Lavendamycin Analogues.
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A three-steps approach to the lavendamycin skeleton from benzene, pyridine and quinoline blocks is described.It is based on a new synthetic methodology for the preparation of α-substituted β-carbolines which involves such reactions as Directed Ortho Metal
- Rocca, Patrick,Marsais, Fracis,Godard, Alain,Queguiner, Guy
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p. 2937 - 2940
(2007/10/02)
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- Hydroxylated inhibitors of HIV reverse transcriptase
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Novel biotransformed or synthetic hydroxy pyridinones inhibit HIV reverse transcriptase, and are useful in the prevention or treatment of infection by HIV and the treatment of AIDS, either as compounds, pharmaceutically acceptable salts (where appropriate
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- Nitro, amino and aroylamino-N-phenylpyridinamines in a process for preparing pyrido[1,4]benzodiazepines
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Nitro, amino and aroylamino-N-phenylpyridinamines as chemical intermediates and/or having antidepressant activity having the formula STR1 wherein R3 is nitro, amino or aroylamino, and Q is hydrogen, --NR1 R2 or halogen are disclosed in a process for preparing pyrido[1,4]benzodiazepines.
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