RESUMEN
We report here the discovery and pharmacological characterization of N-(1-benzyl-1H-pyrazol-3-yl)-2-phenylacetamide derivatives as potent, selective, brain-penetrating T-type calcium channel blockers. Optimization focused mainly on solubility, brain penetration, and the search for an aminopyrazole metabolite that would be negative in an Ames test. This resulted in the preparation and complete characterization of compound 66b (ACT-709478), which has been selected as a clinical candidate.
Asunto(s)
Bencenoacetamidas/química , Bencenoacetamidas/farmacología , Bloqueadores de los Canales de Calcio/química , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo T/metabolismo , Epilepsia Generalizada/tratamiento farmacológico , Animales , Bencenoacetamidas/metabolismo , Bencenoacetamidas/farmacocinética , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Bloqueadores de los Canales de Calcio/metabolismo , Bloqueadores de los Canales de Calcio/farmacocinética , Perros , Descubrimiento de Drogas , Epilepsia Generalizada/metabolismo , Cobayas , Humanos , Macaca fascicularis , Pirazoles/química , Pirazoles/farmacología , Ratas Wistar , Relación Estructura-ActividadRESUMEN
We describe the discovery and optimization of new, brain-penetrant T-type calcium channel blockers. We present optimized compounds with excellent efficacy in a rodent model of generalized absence-like epilepsy. Along the fine optimization of a chemical series with a pharmacological target located in the CNS (target potency, brain penetration, and solubility), we successfully identified an Ames negative aminopyrazole as putative metabolite of this compound series. Our efforts culminated in the selection of compound 20, which was elected as a preclinical candidate.
Asunto(s)
Bloqueadores de los Canales de Calcio/uso terapéutico , Canales de Calcio Tipo T/efectos de los fármacos , Descubrimiento de Drogas , Epilepsia Generalizada/tratamiento farmacológico , Animales , Canales de Calcio Tipo T/fisiología , Modelos Animales de Enfermedad , Humanos , Ratones , RatasRESUMEN
We identified and characterized a series of pyrrole amides as potent, selective Cav3.2-blockers. This series culminated with the identification of pyrrole amides 13b and 26d, with excellent potencies and/or selectivities toward the Cav3.1- and Cav3.3-channels. These compounds display poor physicochemical and DMPK properties, making their use difficult for in vivo applications. Nevertheless, they are well-suited for in vitro studies.
Asunto(s)
Amidas/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo T/metabolismo , Descubrimiento de Drogas , Pirroles/farmacología , Amidas/síntesis química , Amidas/química , Animales , Bloqueadores de los Canales de Calcio/síntesis química , Bloqueadores de los Canales de Calcio/química , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Pirroles/síntesis química , Pirroles/química , Ratas , Relación Estructura-ActividadRESUMEN
We identified and characterized a series of pyrazole amides as potent, selective Cav3.1-blockers. This series culminated with the identification of pyrazole amides 5a and 12d, with excellent potencies and/or selectivities toward the Cav3.2- and Cav3.3-channels. This compound displays poor DMPK properties, making its use difficult for in vivo applications. Nevertheless, this compound as well as analogous ones are well-suited for in vitro studies.
Asunto(s)
Amidas/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo T/metabolismo , Descubrimiento de Drogas , Pirroles/farmacología , Amidas/síntesis química , Amidas/química , Animales , Bloqueadores de los Canales de Calcio/síntesis química , Bloqueadores de los Canales de Calcio/química , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Pirroles/síntesis química , Pirroles/química , Ratas , Relación Estructura-ActividadRESUMEN
Despite the availability of numerous antiepileptic drugs, 20-30% of epileptic patients are pharmacoresistant with seizures not appropriately controlled. Consequently, new strategies to address this unmet medical need are required. T-type calcium channels play a key role in neuronal excitability and burst firing, and selective triple T-type calcium channel blockers could offer a new way to treat various CNS disorders, in particular epilepsy. Herein we describe the identification of new 1,4-benzodiazepines as brain penetrant and selective triple T-type calcium channel blockers. From racemic hit 4, optimization work led to the preparation of pyridodiazepine 31c with improved physicochemical properties, solubility, and metabolic stability. The racemic mixture was separated by chiral preparative HPLC, and the resulting lead compound (3R,5S)-31c showed promising efficacy in the WAG/Rij-rat model of generalized nonconvulsive absence-like epilepsy.
Asunto(s)
Encéfalo/efectos de los fármacos , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo T/metabolismo , Animales , Encéfalo/metabolismo , Bloqueadores de los Canales de Calcio/química , Bloqueadores de los Canales de Calcio/metabolismo , Relación Dosis-Respuesta a Droga , Células HEK293 , Humanos , Masculino , Microsomas Hepáticos/química , Microsomas Hepáticos/metabolismo , Estructura Molecular , Ratas , Ratas Endogámicas , Convulsiones/tratamiento farmacológico , Relación Estructura-ActividadRESUMEN
A series of dihydropyrazole derivatives was developed as potent, selective, and brain-penetrating T-type calcium channel blockers. An optimized derivative, compound 6c, was advanced to in vivo studies, where it demonstrated efficacy in the WAG/Rij rat model of generalized nonconvulsive, absence-like epilepsy. Compound 6c was not efficacious in the basolateral amygdala kindling rat model of temporal lobe epilepsy, and it led to prolongation of the PR interval in ECG recordings in rodents.
Asunto(s)
Anticonvulsivantes/química , Anticonvulsivantes/uso terapéutico , Bloqueadores de los Canales de Calcio/química , Bloqueadores de los Canales de Calcio/uso terapéutico , Epilepsia/tratamiento farmacológico , Pirazoles/química , Pirazoles/uso terapéutico , Animales , Anticonvulsivantes/farmacocinética , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/fisiopatología , Bloqueadores de los Canales de Calcio/farmacocinética , Canales de Calcio Tipo T/metabolismo , Modelos Animales de Enfermedad , Perros , Electroencefalografía , Epilepsia/metabolismo , Epilepsia/fisiopatología , Humanos , Excitación Neurológica/efectos de los fármacos , Masculino , Pirazoles/farmacocinética , Ratas WistarRESUMEN
The discovery of a new series of piperidine-based renin inhibitors is described herein. SAR optimization upon the P3 renin sub-pocket is described, leading to the discovery of 9 and 41, two bioavailable renin inhibitors orally active at low doses in a transgenic rat model of hypertension.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Piperidinas/síntesis química , Piperidinas/farmacología , Renina/antagonistas & inhibidores , Animales , Antihipertensivos/farmacología , Presión Sanguínea/efectos de los fármacos , Citocromo P-450 CYP3A , Inhibidores Enzimáticos del Citocromo P-450 , Diseño de Fármacos , Modelos Moleculares , Piperidinas/química , Conformación Proteica , Ratas , Relación Estructura-Actividad , Difracción de Rayos XRESUMEN
The optimization of the 4-position of recently described new 3,4-disubstituted piperidine-based renin inhibitors is reported herein. The synthesis and characterization of compounds leading to the discovery of 11 (ACT-178882, MK-1597), a renin inhibitor with a suitable profile for development is described.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Piperidinas/síntesis química , Piperidinas/farmacología , Renina/antagonistas & inhibidores , Angiotensinógeno/genética , Animales , Animales Modificados Genéticamente , Citocromo P-450 CYP3A , Inhibidores Enzimáticos del Citocromo P-450 , Inhibidores Enzimáticos/química , Humanos , Indicadores y Reactivos , Modelos Moleculares , Piperidinas/química , Ratas , Renina/genética , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The discovery and SAR of a new series of substituted amino propanamide renin inhibitors are herein described. This work has led to the preparation of compounds with in vitro and in vivo profiles suitable for further development. Specifically, challenges pertaining to oral bioavailability, covalent binding and time-dependent CYP 3A4 inhibition were overcome thereby culminating in the identification of compound 50 as an optimized renin inhibitor with good efficacy in the hypertensive double-transgenic rat model.
Asunto(s)
Antihipertensivos/química , Antihipertensivos/uso terapéutico , Hipertensión/tratamiento farmacológico , Renina/antagonistas & inhibidores , Renina/metabolismo , Animales , Antihipertensivos/farmacología , Presión Sanguínea/efectos de los fármacos , Cristalografía por Rayos X , Perros , Humanos , Modelos Moleculares , Unión Proteica , Ratas , Ratas Sprague-Dawley , Renina/química , Relación Estructura-ActividadRESUMEN
New classes of de novo designed renin inhibitors are reported. Some of these compounds display excellent in vitro and in vivo activities toward human renin in a TGR model. The synthesis of these new types of mono- and bicyclic scaffolds are reported, and properties of selected compounds discussed.
Asunto(s)
Compuestos Bicíclicos con Puentes/clasificación , Compuestos Bicíclicos con Puentes/farmacología , Inhibidores Enzimáticos/clasificación , Inhibidores Enzimáticos/farmacología , Renina/antagonistas & inhibidores , Compuestos Bicíclicos con Puentes/química , Cristalografía por Rayos X , Diseño de Fármacos , Inhibidores Enzimáticos/química , Humanos , Modelos Moleculares , Estructura Molecular , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Starting from known piperidine renin inhibitors, a new series of 3,9-diazabicyclo[3.3.1]nonene derivatives was rationally designed and prepared. Optimization of the positions 3, 6, and 7 of the diazabicyclonene template led to potent renin inhibitors. The substituents attached at the positions 6 and 7 were essential for the binding affinity of these compounds for renin. The introduction of a substituent attached at the position 3 did not modify the binding affinity but allowed the modulation of the ADME properties. Our efforts led to the discovery of compound (+)-26g that inhibits renin with an IC(50) of 0.20 nM in buffer and 19 nM in plasma. The pharmacokinetics properties of this and other similar compounds are discussed. Compound (+)-26g is well absorbed in rats and efficacious at 10 mg/kg in vivo.