RESUMO
N'-methyl-N-(4-tert-butyl-1,2,5,6-tetrahydropyridine)thiourea, SDZ048-619 (1), is a modest inhibitor (IC(50) = 180 microM) of pyruvate dehydrogenase kinase (PDHK). In an optimization of the N-methylcarbothioamide moiety of 1, it was discovered that amides with a small acyl group, in particular appropriately substituted amides of (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid, are inhibitors of PDHK. Utilizing this acyl moiety, herein is reported the rationale leading to the optimization of a series of acylated piperazine derivatives. Methyl substitution of the piperazine at the 2- and 5-positions (with S and R absolute stereochemistry) markedly increased the potency of the lead compound (>1,000-fold). Oral bioavailability of the compounds in this series is good and is optimal (as measured by AUC) when the 4-position of the piperazine is substituted with an electron-poor benzoyl moiety. (+)-1-N-[2,5-(S, R)-Dimethyl-4-N-(4-cyanobenzoyl)piperazine]-(R)-3,3, 3-trifluoro-2-hydroxy-2-methylpropanamide (14e) inhibits PDHK in the primary enzymatic assay with an IC(50) of 16 +/- 2 nM, enhances the oxidation of [(14)C]lactate into (14)CO(2) in human fibroblasts with an EC(50) of 57 +/- 13 nM, diminishes lactate significantly 2.5 h post-oral-dose at doses as low as 1 micromol/kg, and increases the ex vivo activity of PDH in muscle, liver, and fat tissues in normal Sprague-Dawley rats. These PDHK inhibitors, however, do not lower glucose in diabetic animal models.
Assuntos
Inibidores Enzimáticos/farmacologia , Propionatos/farmacologia , Inibidores de Proteínas Quinases , Proteínas Quinases , Amidas , Animais , Área Sob a Curva , Disponibilidade Biológica , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Humanos , Ácido Láctico/sangue , Espectroscopia de Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Propionatos/química , Propionatos/farmacocinética , Proteínas Serina-Treonina Quinases , Piruvato Desidrogenase Quinase de Transferência de Acetil , Ratos , Ratos Sprague-DawleyAssuntos
Amidas/síntese química , Inibidores Enzimáticos/síntese química , Propionatos/síntese química , Inibidores de Proteínas Quinases , Proteínas Quinases , Administração Oral , Amidas/química , Amidas/farmacocinética , Amidas/farmacologia , Animais , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Fibroblastos , Humanos , Técnicas In Vitro , Ácido Láctico/metabolismo , Propionatos/química , Propionatos/farmacocinética , Propionatos/farmacologia , Proteínas Serina-Treonina Quinases , Piruvato Desidrogenase Quinase de Transferência de Acetil , Ratos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The IC50 values of phosphoramidon, CGS 25015, CGS 26129, thiorphan and benazeprilat for inhibition of endothelin converting enzyme partially purified from porcine aortic endothelial cells were 3.5, 18, 58, > 100 and > 100 microM, respectively. A similar rank order of potency was observed for inhibition of the proendothelin-1 (proET-1) -induced pressor response in the rat where phosphoramidon, CGS 25015, CGS 26129, thiorphan and benazeprilat at 30 mg/kg i.v. produced 65, 57, 27, 12, and 0% inhibition, respectively. A slightly different rank order of potency was obtained in the proET-induced contraction of porcine coronary arteries where IC50 values of < 10, 10-30, 10-30, 30-100 and 30-100 microM were exhibited by CGS 25015, CGS 26129, phosphoramidon, thiorphan and benazeprilat, respectively. These data indicate that the endothelin converting enzymes in the three systems studied are similar, except that phosphoramidon is a slightly more potent inhibitor in the in vitro assay and the in vivo pressor test than in the smooth muscle contraction assay.
Assuntos
Ácido Aspártico Endopeptidases/metabolismo , Endotelinas/metabolismo , Neprilisina/antagonistas & inibidores , Precursores de Proteínas/metabolismo , Animais , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Benzazepinas/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Vasos Coronários/efeitos dos fármacos , Relação Dose-Resposta a Droga , Endotelina-1 , Enzimas Conversoras de Endotelina , Endotelinas/farmacologia , Endotélio Vascular/enzimologia , Glicopeptídeos/farmacologia , Técnicas In Vitro , Masculino , Metaloendopeptidases , Metionina/análogos & derivados , Metionina/farmacologia , Contração Muscular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Propionatos/farmacologia , Precursores de Proteínas/farmacologia , Ratos , Ratos Sprague-Dawley , Suínos , Tiorfano/farmacologiaRESUMO
A series of 13- and 14-membered ring lactam derivatives 9a,b, 10, 11, and 12a-c was prepared from L-cysteine. Compounds 9a,b and 12a,b were tested in vitro for inhibition of neutral endopeptidase 24.11 (NEP) and angiotensin converting enzyme (ACE) inhibition. The structure-activity profile of the series is discussed. Compound 9b, a 13-membered ring macrocyclic lactam, had an NEP IC50 of 18 nM and an ACEIC50 of 12 nM in vitro and showed dual plasma inhibition after intravenous or oral administration.