RESUMO
Like other nonnucleoside inhibitors of HIV-1 reverse transcriptase, the dipyridodiazepinone nevirapine (Viramune, 1) selects for drug resistant variants of HIV-1, both in cell culture and in patients. In particular, the mutation of residue 181 from tyrosine to cysteine (Y181C) is associated with resistance to most reported nonnucleoside inhibitors. Introduction of an arylethyl substituent at the 8-position of the tricyclic dipyridodiazepinone skeleton confers enhanced potency against Y181C RT. Several analogues of this series display good broad spectrum potency against a panel of mutant enzymes.
Assuntos
Antivirais/síntese química , Azepinas/síntese química , Transcriptase Reversa do HIV/antagonistas & inibidores , Mutação , Piridinas/síntese química , Inibidores da Transcriptase Reversa/síntese química , Substituição de Aminoácidos , Antivirais/química , Antivirais/farmacologia , Azepinas/química , Azepinas/farmacologia , Linhagem Celular Transformada , Resistência Microbiana a Medicamentos , Transcriptase Reversa do HIV/genética , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , HIV-1/genética , Humanos , Técnicas In Vitro , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Nevirapina/química , Nevirapina/farmacologia , Piridinas/química , Piridinas/farmacologia , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacologia , Relação Estrutura-AtividadeRESUMO
Nevirapine (I) is the first human immunodeficiency virus type 1 (HIV-1) nonnucleoside reverse transcriptase (RT) inhibitor to reach regulatory approval. As a result of a second generation program around the tricyclic core system of nevirapine, 2-chloro-5, 11-dihydro-11-ethyl-5-methyl-8-(2-(pyridin-4-yl)ethyl)-6H-dipyrido[3, 2-b:2',3'-e][1,4]diazepin-6-one (II)1a and 2-chloro-5, 11-dihydro-11-ethyl-5-methyl-8-phenylethyl-6H-dipyrido[3,2-b:2', 3'-e][1,4]diazepin-6-one (III)1a were identified as broad spectrum HIV-1 RT inhibitors. A detailed examination of replacing either of the methylenes of the 8-ethyl linker of II or III is presented. It was found that 8-aryloxymethyl and 8-arylthiomethyl are the preferred pattern of substitution for potency against RT. The most potent compounds were further evaluated against a panel of clinically significant mutant RT enzymes (K103N, V106A, G190A, P236L) and in cytotoxicity and in vitro metabolism assays. The most potent compound was 2-chloro-8-phenylthiomethyl analogue 37 which displayed sub-100 nM activity against all HIV-1 RT enzymes tested.
Assuntos
Antivirais/síntese química , Azepinas/síntese química , Transcriptase Reversa do HIV/antagonistas & inibidores , Nevirapina/análogos & derivados , Piridinas/síntese química , Inibidores da Transcriptase Reversa/síntese química , Animais , Antivirais/química , Antivirais/farmacologia , Azepinas/química , Azepinas/farmacologia , Disponibilidade Biológica , Linhagem Celular Transformada , Sobrevivência Celular/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Resistência Microbiana a Medicamentos , Estabilidade de Medicamentos , Transcriptase Reversa do HIV/genética , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , HIV-1/fisiologia , Humanos , Técnicas In Vitro , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Mutação , Nevirapina/síntese química , Nevirapina/química , Nevirapina/farmacocinética , Nevirapina/farmacologia , Piridinas/química , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacologia , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacosRESUMO
Potent and selective dipeptidyl boronic acid proteasome inhibitors are described. As compared to peptidyl aldehyde compounds, boronic acids in this series display dramatically enhanced potency. Compounds such as 15 are promising new therapeutics for treatment of cancer and inflammatory diseases.
Assuntos
Ácidos Borônicos/farmacologia , Cisteína Endopeptidases/efeitos dos fármacos , Complexos Multienzimáticos/efeitos dos fármacos , Inibidores de Proteases/farmacologia , Ácidos Borônicos/química , Estrutura Molecular , Inibidores de Proteases/química , Complexo de Endopeptidases do ProteassomaRESUMO
Dibenz[b,f][1,4]oxazepin-11(10H)-ones (III), pyrido[2,3-b][1,4]benzoxazepin-6(5H)-ones (IV), and pyrido[2,3-b]- [1,5]benzoxazepin-5(6H)-ones (V) were found to inhibit human immunodeficiency virus type 1 reverse transcriptase with IC50 values as low as 19 nM. A-ring substitution has a profound effect on activity, with appropriate substituents at the positions ortho and para to the lactam nitrogen providing dramatically enhanced potency. Substitution in the C-ring is generally neutral or detrimental to activity. Although a C-ring amino substituent at the position meta to the lactam carbonyl is generally beneficial to activity, it has essentially no effect when the A-ring is optimally substituted. Like the dipyridodiazepinone nevirapine, compounds III-V are specific for HIV-1 RT, exhibiting no inhibitory activity against HIV-2 RT or other virial reverse transcriptase enzymes.