RESUMEN
Efficient parallel synthesis of novel 7-oxa-steroids 4 has been achieved from the key intermediate 3 via a one-pot four-step sequence. oxa-Steroids 4 with various ortho-, meta-, and para-monosubstituents on the phenyl ring, as well as disubstituted phenyl and heterocycles, were evaluated for progesterone receptor (PR) and glucocorticoid receptor (GR) antagonist activities. SAR study demonstrated that the para-fluorinated substituents on the phenyl ring not only increased the potency for PR in a T47D cell functional assay, but also improved the selectivity over GR in an A549 cell functional assay. The para-fluorophenyl oxa-steroid 4l and the para-trifluoromethylphenyl oxa-steroid 4p were found to be remarkably more potent and more selective PR antagonists than mifepristone, with subnanomolar potency and about 140-fold selectivity over GR. Molecular modeling of the oxa-steroid bound to PR provided meaningful insight for the SAR study. oxa-Steroids 4a and 4b were found to be more efficacious than mifepristone in vivo in a rat uterine complement C3 assay via the oral route, although they were less than or equally potent to mifepristone in the T47D assay.
Asunto(s)
Química Farmacéutica/métodos , Receptores de Progesterona/antagonistas & inhibidores , Esteroides/química , Animales , Línea Celular Tumoral , Complemento C3/metabolismo , Diseño de Fármacos , Femenino , Humanos , Mifepristona/farmacología , Modelos Químicos , Unión Proteica , Ratas , Receptores de Glucocorticoides/antagonistas & inhibidores , Relación Estructura-ActividadRESUMEN
The synthesis and in vivo SAR of 5,6-dichloro-benzimidazole derivatives as novel selective androgen receptor antagonists are described. During screening of 2-alkyl benzimidazoles, it was found that a trifluoromethyl group greatly enhances antagonist activity in the prostate. Benzimidazole 1 is a potent AR antagonist in the rat prostate (ID50 = 0.15 mg/day).
Asunto(s)
Antagonistas de Andrógenos/síntesis química , Antagonistas de Andrógenos/farmacología , Antagonistas de Receptores Androgénicos , Bencimidazoles/síntesis química , Bencimidazoles/farmacología , Animales , Indicadores y Reactivos , Masculino , Peso Molecular , Orquiectomía , Próstata/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Sulfuros/síntesis química , Sulfonas/síntesis químicaRESUMEN
A novel series of oxa-steroids 6 derived from (8S, 13S, 14R)-7-oxa-estra-4,9-diene-3,17-dione 1 have been synthesized and identified as potent and selective progesterone receptor antagonists. These novel oxa-steroids showed similar potency to mifepristone. Preliminary SAR study resulted in the most potent 17-phenylethynyl oxa-steroid 6i wih an IC(50) of 1.4nM. In contrast to the equipotent mifepristone toward the progesterone receptor (PR) and glucocorticoid receptor (GR), compound 6i had over 200-fold selectivity for PR over GR.
Asunto(s)
Receptores de Progesterona/antagonistas & inhibidores , Esteroides/síntesis química , Esteroides/farmacología , Fosfatasa Alcalina/biosíntesis , Neoplasias de la Mama/enzimología , Línea Celular Tumoral , Inducción Enzimática/efectos de los fármacos , Femenino , Genes Reporteros/efectos de los fármacos , Antagonistas de Hormonas/síntesis química , Antagonistas de Hormonas/farmacología , Humanos , Mifepristona/síntesis química , Mifepristona/farmacología , Receptores de Glucocorticoides/efectos de los fármacos , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The synthesis and in vivo SAR of N-benzyl, N-aceto, and N-ethylene ether derivatives of 2-(2,2,2-trifluoroethyl)-5,6-dichloro-benzimidazole as novel androgen receptor antagonists are described. SAR studies led to the discovery of 4-bromo-benzyl benzimidazole 17 as a more potent androgen receptor antagonist in the rat prostate (ID(50)=0.13mg/day), compared with bicalutamide (ID(50)=0.23mg/day).
Asunto(s)
Antagonistas de Andrógenos/síntesis química , Antagonistas de Andrógenos/farmacología , Antagonistas de Receptores Androgénicos , Antineoplásicos Hormonales/síntesis química , Antineoplásicos Hormonales/farmacología , Bencimidazoles/síntesis química , Bencimidazoles/farmacología , Alquilación , Anilidas/farmacología , Animales , Indicadores y Reactivos , Masculino , Nitrilos/farmacología , Orquiectomía , Tamaño de los Órganos/efectos de los fármacos , Próstata/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Compuestos de Tosilo/farmacologíaRESUMEN
We previously reported a series of potent and selective pyrimidinyl pyrroloquinolone PDE5 inhibitors such as 2a for potential use in male erectile dysfunction (MED) (Sui, Z.; Guan, J.; Macielag, M. J.; Jiang, W.; Zhang, S.; Qiu, Y.; Kraft, P., Bhattacharjee, S.; John, T. M.; Craig, E.; Haynes-Johnson, D.; Clancy, J. J. Med. Chem. 2002, 45, 4094-4096). Unfortunately, the low aqueous solubility and poor oral bioavailability rendered them undesirable development candidates. To address this issue, we designed a series of analogues using two approaches: increasing the overall basicity and reducing molecular weight of the lead. Through earlier SAR studies, we discovered that the PDE5 potency of the pyrroloquinolones is insensitive to substitution on the pyrrole nitrogen. Basic functional groups such as pyridines and benzimidazoles were appended via the aromatic ring connected to the pyrrole nitrogen. Several truncated analogues were also designed and synthesized to improve oral absorption. These modifications allowed us to identify analogues with good oral bioavailability in rats, dogs, and monkeys while the high potency against PDE5 and desirable selectivity versus other PDE isozymes were maintained. Compounds R-11e and R-11l were selected as development candidates for MED and other indications.
Asunto(s)
3',5'-GMP Cíclico Fosfodiesterasas/antagonistas & inhibidores , Pirroles/síntesis química , Quinolonas/síntesis química , Animales , Disponibilidad Biológica , Presión Sanguínea/efectos de los fármacos , Línea Celular , GMP Cíclico/biosíntesis , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5 , Perros , Estimulación Eléctrica , Disfunción Eréctil/tratamiento farmacológico , Macaca mulatta , Masculino , Pene/irrigación sanguínea , Pene/efectos de los fármacos , Pirroles/farmacocinética , Pirroles/farmacología , Quinolonas/farmacocinética , Quinolonas/farmacología , Ratas , Ratas Sprague-Dawley , Solubilidad , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
We have characterized a novel, potent, and selective phosphodiesterase type 5 inhibitor, JNJ-10258859 ((R)-(-)-3-(2,3-dihydro-benzofuran-5-yl)-2-[5-(4-methoxy-phenyl)-pyrimidin-2-yl]-1,2,3,4-tetrahydro-pyrrolo[3,4-b]quinolin-9-one). Its inhibitory effects on phosphodiesterase 1-6 were determined using enzymes partially purified from human tissues. The compound inhibited phosphodiesterase type 5 with a K(i) of 0.23 nM and displayed excellent selectivity versus phosphodiesterase types 1-4 (>/=22,000 fold compared to phosphodiesterase type 5). It had 27-fold selectivity over phosphodiesterase type 6 as well. In a cell-based assay, JNJ-10258859 was more potent than sildenafil in potentiating nitric oxide (NO) induced accumulation of intracellular cGMP. The in vivo effect of JNJ-10258859 was evaluated in an anesthetized dog model via intravenous administration. The compound had similar efficacy to sildenafil in enhancing both the amplitude and duration of intracavernosal pressure increase induced by electrical stimulation to the pelvic nerve. No significant effects on either mean aortic pressure or heart rate were observed during the course of the experiments. This data suggests that JNJ-10258859 could be a useful treatment for erectile dysfunction.
Asunto(s)
Erección Peniana/efectos de los fármacos , Inhibidores de Fosfodiesterasa/farmacología , Hidrolasas Diéster Fosfóricas/metabolismo , Quinolonas/farmacología , 3',5'-GMP Cíclico Fosfodiesterasas , Animales , Plaquetas/enzimología , Línea Celular , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5 , Perros , Relación Dosis-Respuesta a Droga , Estimulación Eléctrica , Humanos , Masculino , Músculo Esquelético/enzimología , Miocardio/enzimología , Pene/efectos de los fármacos , Pene/enzimología , Pene/inervación , Pene/metabolismo , Hidrolasas Diéster Fosfóricas/aislamiento & purificación , Piperazinas/farmacología , Purinas , Ratas , Retina/enzimología , Citrato de Sildenafil , Especificidad por Sustrato , SulfonasRESUMEN
A series of N(2)-furoyl and N(2)pyrimidinyl beta-carbolines was discovered to possess potent inhibitory activity against PDE5. During the synthesis we developed a tandem resin quenching protocol, which allowed us to synthesize large number of target compounds in a rapid fashion. Representative compounds exhibit superior selectivity to sildenafil versus other isozymes of PDEs, and demonstrated in vivo efficacy in increasing introcavernosal pressure in dogs.
Asunto(s)
3',5'-GMP Cíclico Fosfodiesterasas/antagonistas & inhibidores , Carbolinas/síntesis química , Carbolinas/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Técnicas Químicas Combinatorias/métodos , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5 , Perros , Evaluación Preclínica de Medicamentos , Disfunción Eréctil/tratamiento farmacológico , Humanos , Isoenzimas , Masculino , Pene/efectos de los fármacos , Piperazinas , Purinas , Citrato de Sildenafil , Solubilidad , Relación Estructura-Actividad , SulfonasRESUMEN
Synthesis of furoyl and benzofuroyl pyrroloquinolones as potent and selective PDE5 inhibitors was reported. Their in vitro potencies in inhibiting PDE5 and selectivity in inhibiting other PDE isozymes (PDE1-4 and PDE6) were evaluated. Some of these compounds are more potent than sildenafil with better selectivity toward PDE1 and PDE6. Incorporation of solublizing groups resulted in bioavailable analogues. Selected compounds showed in vivo efficacy in anesthetized dog model for penile erection.
Asunto(s)
3',5'-GMP Cíclico Fosfodiesterasas/antagonistas & inhibidores , Furanos/síntesis química , Quinolonas/síntesis química , Animales , Disponibilidad Biológica , Línea Celular , GMP Cíclico/biosíntesis , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5 , Perros , Disfunción Eréctil/tratamiento farmacológico , Furanos/química , Furanos/farmacología , Isoenzimas/antagonistas & inhibidores , Masculino , Erección Peniana/efectos de los fármacos , Quinolonas/química , Quinolonas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
A series of N-pyrimidinylpyrroloquinolones were discovered as extremely potent and selective PDE5 inhibitors. Representative compounds demonstrated in vivo efficacy in dog erectile dysfunction models and are orally bioavailable.