RESUMO
A series of 8-heteroarylthiomethyldipyridodiazepinone derivatives were prepared and evaluated for their antiviral profile against wild type virus and the important K103N/Y181C mutant as an indicator for broad activity. 2,6-Dimethylpyridine derivative 16 was found to have a good pharmacokinetic profile in spite of poor metabolic stability in rat liver microsomes.
Assuntos
Fármacos Anti-HIV , Azepinas , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Nevirapina/síntese química , Inibidores da Transcriptase Reversa , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/metabolismo , Fármacos Anti-HIV/farmacologia , Azepinas/síntese química , Azepinas/metabolismo , Azepinas/farmacologia , Farmacorresistência Viral , Infecções por HIV/virologia , Transcriptase Reversa do HIV/química , HIV-1/enzimologia , HIV-1/genética , Humanos , Taxa de Depuração Metabólica , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Mutação , Nevirapina/farmacologia , Piridinas/síntese química , Piridinas/metabolismo , Piridinas/farmacologia , Ratos , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/metabolismo , Inibidores da Transcriptase Reversa/farmacologia , Relação Estrutura-AtividadeRESUMO
The work described herein considers the impact of stereoelectronic effects and allylic 1,3-strain in controlling the cyclofunctionalization reaction when a hydroxyl group is at the allylic position. The stereoelectronic arguments are supported by independent iodocyclization reactions performed using two secondary alcohols. The transition-state pathways involved in these reactions are established through a comparison of relative reaction rates. A bi-directional approach is used to demonstrate the potential of the iodocyclization reaction to differentiate a terminus in molecules with a pseudo C(2) axis of symmetry, showing that two-directional synthesis can be used to differentiate between alternative transition-state pathways.
RESUMO
A series of monobactam inhibitors of HCMV (N(o)) protease bearing a heterocycle linked by a methylene group at C-4 is described. Inhibitors containing a heterocycle such as a 2-furyl, 2-thiophenyl, 4-methyl-2-tetrazole and 2-benzothiazole were found to be active in a plaque reduction assay. Furthermore, 2-benzothiazole derivatives were shown to inhibit the HCMV protease activity inside cells by using a cell transfection assay, indicating that their antiviral activity in the plaque reduction assay could be attributed to protease inhibition.
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Citomegalovirus/efeitos dos fármacos , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Serina Endopeptidases/efeitos dos fármacos , Animais , Antivirais/química , Células COS , Citomegalovirus/enzimologia , Citomegalovirus/crescimento & desenvolvimento , Monobactamas/síntese química , Monobactamas/química , Monobactamas/farmacologia , Inibidores de Proteases/química , Análise Espectral , Ensaio de Placa ViralRESUMO
A new series of non-peptidic renin inhibitors having a 2-substituted butanediamide moiety at the P2 and P3 positions has been identified. The optimized inhibitors have IC50 values of 0.8 to 1.4 nM and 2.5 to 7.6 nM in plasma renin assays at pH 6.0 and 7.4, respectively. When evaluated in the normotensive cynomolgus monkey model, two of the most potent inhibitors were orally active at a dose as low as 3 mg/kg. These potent renin inhibitors are characterized by oral bioavailabilities of 40 and 89% in the cynomolgus monkey. Inhibitor 3z (BILA 2157 BS) was selected as candidate for pre-development.
Assuntos
Amidas/química , Renina/antagonistas & inibidores , Administração Oral , Amidas/farmacocinética , Amidas/farmacologia , Animais , Disponibilidade Biológica , Humanos , Macaca fascicularis , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Estrutura Molecular , Renina/sangue , Espectrofotometria Infravermelho , Relação Estrutura-AtividadeRESUMO
The development of novel monobactam inhibitors of HCMV protease incorporating a carbon side chain at C-4 and a urea function at N-1 is described. Substitution with small groups at the C-3 position of the beta-lactam ring gave an increase in enzymatic activity and in stability; however, a lack of selectivity against other serine proteases was noted. The use of both tri- and tetrasubstituted urea functionalities gave effective inhibitors of HCMV protease. Benzyl substitution of the urea moiety was beneficial, especially when strong electron-withdrawing groups where attached at the para position. Modest antiviral activity was found in a plaque reduction assay.
Assuntos
Antivirais , Citomegalovirus/efeitos dos fármacos , Serina Endopeptidases/metabolismo , Inibidores de Serina Proteinase , Ureia , beta-Lactamas , Animais , Antivirais/síntese química , Antivirais/química , Antivirais/farmacologia , Bovinos , Linhagem Celular Transformada , Citomegalovirus/enzimologia , Citomegalovirus/fisiologia , Humanos , Inibidores de Serina Proteinase/síntese química , Inibidores de Serina Proteinase/química , Inibidores de Serina Proteinase/farmacologia , Relação Estrutura-Atividade , Suínos , Ureia/análogos & derivados , Ureia/síntese química , Ureia/química , Ureia/farmacologia , beta-Lactamas/síntese química , beta-Lactamas/química , beta-Lactamas/farmacologiaRESUMO
A series of novel monobactam inhibitors of human cytomegalovirus (HCMV) protease has been described that possess a heterocyclic thiomethyl side chain at C-4. Changes to the heterocycle did not significantly change the inhibitory activity of these compounds in an enzymatic assay, although improvements in solubility and cell culture activity were noted. A number of permutations between C-4 substitutions and N-1 derivatives led to the identification of several beta-lactams with antiviral activity in a plaque reduction assay. N-methyl thiotetrazole-containing compounds were found to be the most potent inhibitors in the enzymatic assay.
Assuntos
Citomegalovirus/enzimologia , beta-Lactamas/síntese química , Antivirais/síntese química , Antivirais/farmacologia , Citomegalovirus/efeitos dos fármacos , Desenho de Fármacos , Humanos , Estrutura Molecular , Inibidores de Serina Proteinase/síntese química , Inibidores de Serina Proteinase/farmacologia , Tetrazóis/síntese química , Tetrazóis/farmacologia , Ureia/análogos & derivados , Proteínas Virais/metabolismo , beta-Lactamas/farmacologiaRESUMO
A series of N-tert-butylacetyl-l-tert-butylglycyl-l-Ngamma, Ngamma-dimethylasparagyl-l-alanyl-derived inhibitors (trifluoromethyl ketone 1, pentafluoroethyl ketone, 2, methyl ketone 3, and alpha-ketoamide 4, with respective KI values of 1.1, 0.1, 2100, and 0.2 microM) of the human cytomegalovirus protease were used to study the effect of binding of peptidyl inhibitors on the intrinsic fluorescence and CD properties of the enzyme. In the presence of saturating concentrations of compounds 1, 2, and 4, an identical blue shift in the fluorescence maximum of the enzyme upon specific tryptophan excitation was observed relative to that of the free protease. In the case of the methyl ketone 3, whose inhibition of the enzyme does not involve formation of a covalent adduct as evidenced by 13C NMR studies of carbonyl-labeled inhibitors, the blue shift in the emission was also observed. For both compounds 1 and 2 which exhibit slow-binding kinetics, the observed rate constants for the slow onset of inhibition of substrate hydrolysis correlate well with the kobs values of the time-dependent change in the emission spectra. Studies employing a double mutant of HCMV protease Ala143Gln/Trp42Phe identified Trp-42 as the principal fluorescence reporter. Taken together with information provided by our recent elucidation of the crystallographic structure of the enzyme [Tong, L., Qian, C., Massariol, M.-J., Bonneau, P. R., Cordingley, M. G., & Lagacé, L. (1996) Nature 383, 272], these observations are consistent with the inhibition of HCMV protease by peptidyl ketones involving a conformational change of the protease. A mechanism involving a kon limited by dehydration of the hydrated species, followed by rapid ligand binding and a conformational change prior to covalent adduct formation, is proposed for activated inhibitors such as 1 and 2.