RESUMEN
We report synthesis and optimization of a series of (3S,5R)-5-(2,2-dimethyl-5-oxo-4-phenylpiperazin-1-yl)piperidine-3-carboxamides as renin inhibitors. Chemical modification of P1', P2' and P3 portions led to a promising 3,5-disubstituted piperidine 32o showing high renin inhibitory activity and favorable oral exposure in both rats and cynomolgus monkeys with acceptable CYP and hERG current inhibition. Compound 32o exhibited a significant blood pressure lowering effect by oral administration in two hypertensive animal models, double transgenic rats and furosemide pretreated cynomolgus monkeys.
Asunto(s)
Amidas/química , Piperazinas/síntesis química , Piperidinas/química , Piperidinas/síntesis química , Inhibidores de Proteasas/síntesis química , Renina/antagonistas & inhibidores , Administración Oral , Amidas/farmacocinética , Amidas/uso terapéutico , Animales , Presión Sanguínea/efectos de los fármacos , Modelos Animales de Enfermedad , Furosemida/farmacología , Semivida , Hipertensión/tratamiento farmacológico , Macaca fascicularis , Piperazinas/farmacocinética , Piperazinas/uso terapéutico , Piperidinas/farmacocinética , Piperidinas/uso terapéutico , Inhibidores de Proteasas/farmacocinética , Inhibidores de Proteasas/uso terapéutico , Ratas , Ratas Transgénicas , Renina/metabolismo , Relación Estructura-ActividadRESUMEN
With the aim to address an undesired cardiac issue observed with our related compound in the recently disclosed novel series of renin inhibitors, further chemical modifications of this series were performed. Extensive structure-activity relationships studies as well as in vivo cardiac studies using the electrophysiology rat model led to the discovery of clinical candidate trans-adamantan-1-ol analogue 56 (DS-8108b) as a potent renin inhibitor with reduced potential cardiac risk. Oral administration of single doses of 3 and 10 mg/kg of 56 in cynomolgus monkeys pre-treated with furosemide led to significant reduction of mean arterial blood pressure for more than 12 h.
Asunto(s)
Antihipertensivos/síntesis química , Arritmias Cardíacas/prevención & control , Corazón/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Piperazinas/síntesis química , Inhibidores de Proteasas/síntesis química , Renina/antagonistas & inhibidores , Administración Oral , Animales , Antihipertensivos/farmacocinética , Antihipertensivos/farmacología , Presión Arterial/efectos de los fármacos , Femenino , Corazón/fisiopatología , Humanos , Hipertensión/enzimología , Hipertensión/fisiopatología , Macaca fascicularis , Masculino , Técnicas de Cultivo de Órganos , Piperazinas/farmacocinética , Piperazinas/farmacología , Inhibidores de Proteasas/farmacocinética , Inhibidores de Proteasas/farmacología , Conejos , Ratas , Renina/química , Renina/metabolismo , Relación Estructura-ActividadRESUMEN
Introduction of the 2,2-dimethyl-4-phenylpiperazin-5-one scaffold into the P(3)-P(1) portion of the (2S,4S,5S)-5-amino-6-dialkylamino-4-hydroxy-2-isopropylhexanamide backbone dramatically increased the renin inhibitory activity without using the interaction to the S(3)(sp) pocket. Compound 31 exhibited >10,000-fold selectivity over other human proteases, and 18.5% oral bioavailability in monkey.
Asunto(s)
Amidas/química , Piperazinas/química , Renina/antagonistas & inhibidores , Amidas/farmacología , Aminación , Diseño de Fármacos , Hidroxilación , Metilación , Modelos Moleculares , Piperazina , Relación Estructura-ActividadRESUMEN
Utilizing X-ray crystal structure analysis, (3S,5R)-5-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]piperidine-3-carboxamides were designed and identified as renin inhibitors. The most potent compound 15 demonstrated favorable pharmacokinetic and pharmacodynamic profiles in rat.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Descubrimiento de Drogas , Piperazinas/farmacología , Piperidinas/farmacología , Renina/antagonistas & inhibidores , Inhibidores de la Enzima Convertidora de Angiotensina/síntesis química , Inhibidores de la Enzima Convertidora de Angiotensina/química , Animales , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Haplorrinos , Humanos , Modelos Moleculares , Conformación Molecular , Piperazinas/síntesis química , Piperazinas/química , Piperidinas/síntesis química , Piperidinas/química , Renina/sangre , Renina/metabolismo , Relación Estructura-ActividadRESUMEN
A novel orally bioavailable renin inhibitor, DS-8108b (5), showing potent renin inhibitory activity and excellent in vivo efficacy is described. We report herein the synthesis and pharmacological effects of 5 including renin inhibitory activity in vitro, suppressive effects of ex vivo plasma renin activity (PRA) in cynomolgus monkey, pharmacokinetic data, and blood pressure-lowering effects in an animal model. Compound 5 demonstrated inhibitory activities toward human renin (IC50 = 0.9 nM) and human and monkey PRA (IC50 = 1.9 and 6.3 nM, respectively). Oral administration of single doses of 3 and 10 mg/kg of 5 in cynomolgus monkey on pretreatment with furosemide led to dose-dependent significant reductions in ex vivo PRA and sustained lowering of mean arterial blood pressure for more than 12 h.
RESUMEN
To estimate the preventive potential of Japanese rice bran (Oryza sativa japonica) against the oxygen radical-related chronic diseases such as cardio-vascular diseases and cancer, antioxidative and antigenotoxic activities of the rice bran extracts were analyzed by using assay systems for lipid peroxidation and genotoxin-induced umu gene expression. When effects of the rice bran extracts under different extraction conditions on hydroperoxide generation from auto-oxidized linoleic acid were examined using aluminum chloride method, the water extract showed strong antioxidant activity, but the methanol and acetone extracts did not exhibit significant activity. The water extract of rice bran was divided into the ethanol-precipitable (EP) and supernatant fractions, and EP fraction showed the dominant antioxidant activity, but the supernatant fraction did not exhibit significant antioxidant activity. When the effect of EP fraction on umu C gene expression in SOS response associated with DNA damage in Salmonella typhimurium (TA 1535/pSK 1002) induced by 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) was analyzed, it showed a dose-dependent suppressive activity against Trp-P-1-induced umu C gene expression. The bio-chemical analysis of EP fraction indicates that the major antioxidative and antigenotoxic activity of EP fraction is associated with a proteinous component with the molecular weight of more than 30 KDa. As a possible active principle for the antioxidative and antigenotoxic activity in EP fraction, the strong activity of an oxygen radical-scavenging enzyme, peroxidase was detected, and the purified horseradish peroxidase also caused the similar antioxidative and antigenotoxic activities. The significance of this finding is discussed from the viewpoint of the preventive role of rice bran against oxygen radical-related chronic diseases.