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 human renin infused rat model (HRIRM) was used as an in vivo small-animal model for evaluating the efficacy of a collection of inhibitors of human renin. The intravenous infusion of recombinant human renin (2.4 microg x kg(-1) x min(-1)) in the ganglion-blocked, nephrectomized rat produced a mean blood pressor response of 47+/-3 mm Hg (1 mm Hg = 133.3 Pa), which was reduced by captopril, enalkiren, and losartan in a dose-dependent manner following oral administration, with ED50 values of 0.3+/-0.1, 2.5+/-0.9, and 5.2+/-1.6 mg/kg, respectively. A series of peptidomimetic P2-P3 butanediamide renin inhibitors inhibited purified recombinant human renin in vitro in a concentration-dependent manner, with IC50 values ranging from 0.4 to 20 nM at pH 6.0, with a higher range of IC50 values (0.8-80 nM) observed at pH 7.4. Following i.v. administration of renin inhibitors, the pressor response to infused human renin in the HRIRM was inhibited in a dose-dependent manner, with ED50 values ranging from 4 to 600 microg/kg. The in vivo inhibition of human renin following i.v. administration in the rat correlated significantly better with the in vitro inhibition of human renin at pH 7.4 (r = 0.8) compared with pH 6.0 (r = 0.5). Oral administration of renin inhibitors also resulted in a dose-dependent inhibition of the pressor response to infused human renin, with ED50 values ranging from 0.4 to 6.0 mg/kg and the identification of six renin inhibitors with an oral potency of <1 mg/kg. The ED50 of renin inhibitors for inhibition of angiotensin I formation in vivo was highly correlated (r = 0.9) with the ED50 for inhibition of the pressor response. These results demonstrate the high potency, dose dependence, and availability following oral administration of the butanediamide series of renin inhibitors.
Assuntos
Renina/antagonistas & inibidores , Administração Oral , Angiotensina I/biossíntese , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Captopril/farmacologia , Dipeptídeos/farmacologia , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Bloqueadores Ganglionares/farmacologia , Humanos , Técnicas In Vitro , Losartan/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/farmacologia , Renina/farmacologia , Fatores de TempoRESUMO
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
Renin inhibitors containing a 4,5- or a 3,5-dihydroxy-2-substituted-6-phenylhexanamide fragment at the P2-P3 sites have been prepared and evaluated. The four possible diastereomeric diols of the two series of inhibitors were synthesized to determine the optimal configuration of the carbinol centers for these replacements. The most potent inhibitors of each series, la and 2c have a molecular weight of only 503 and IC50 values of 23 and 20 nM in a human plasma renin assay at pH 6.0. Their very low aqueous solubility limited their further evaluation. The efficacy of these P2-P3 replacements is a result of their ability to maintain the important hydrogen-bonds with the enzyme. Due to conformational differences with the dipeptide, adjustment at the P2 side chain was required. These 4,5- and 3,5-dihydroxyhexanamide segments could be seen as novel N-terminal dipeptide replacements.
Assuntos
Amidas/síntese química , Inibidores de Proteases/síntese química , Renina/antagonistas & inibidores , Amidas/química , Amidas/farmacologia , Humanos , Indicadores e Reagentes , Cinética , Conformação Molecular , Estrutura Molecular , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Renina/sangue , Solubilidade , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The binding modes of three peptidomimetic P2-P3 butanediamide renin inhibitors have been determined by x-ray crystallography. The inhibitors are bound with their backbones in an extended conformation, and their side chains occupying the S5 to S1' pockets. A (2-amino-4-thiazolyl)methyl side chain at the P2 position shows stronger hydrogen-bonding and van der Waals interactions with renin than the His side chain, which is present in the natural substrate. The ACHPA-gamma-lactam transition state analog has similar interactions with renin as the dihydroxyethylene transition state analog.