RESUMEN
T-type calcium channel antagonists were designed using a protocol involving the program SPROUT and constrained by a ComFA-based pharmacophore model. Scaffolds generated by SPROUT were evaluated based on their ability to be translated into structures that were synthetically tractable. From this exercise, a novel series of potent and selective T-type channel antagonists containing a biaryl sulfonamide core were discovered.
Asunto(s)
Bloqueadores de los Canales de Calcio/química , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo T/efectos de los fármacos , Sulfonamidas/química , Sulfonamidas/farmacología , Animales , Cristalografía por Rayos X , Diseño de Fármacos , Técnicas In Vitro , Técnicas de Placa-Clamp , Relación Estructura-ActividadRESUMEN
In a continuing effort to discover novel chemotypes as potent and selective PDE5 inhibitors for the treatment of male erectile dysfunction (ED), we have found that 4-benzylaminoquinoline derivatives are very potent and selective PDE5 inhibitors. Some compounds in this series had PDE5 IC(50)'s as low as 50 pM. While an electron withdrawing group at the C6-position of the quinoline substantially improved PDE5 potency, an ethyl group at the C8-position not only improved the PDE5 potency but also the isozyme selectivity. Substitutents at the C3-position can incorporate a variety of different groups. The synthesis and primary structure-activity relationship of this new series of potent PDE5 inhibitors are described.
Asunto(s)
3',5'-GMP Cíclico Fosfodiesterasas/antagonistas & inhibidores , Disfunción Eréctil/tratamiento farmacológico , Inhibidores de Fosfodiesterasa/farmacología , Quinolinas/farmacología , 3',5'-GMP Cíclico Fosfodiesterasas/metabolismo , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 5 , Disfunción Eréctil/enzimología , Humanos , Masculino , Inhibidores de Fosfodiesterasa/química , Inhibidores de Fosfodiesterasa/uso terapéutico , Quinolinas/química , Quinolinas/uso terapéuticoRESUMEN
Class III anti-arrhythmic drugs (e.g., dofetilide) prolong cardiac action potential duration (APD) by blocking the fast component of the delayed rectifier potassium current (I(Kr)). The block of I(Kr) can result in life threatening ventricular arrhythmias (i.e., torsades de pointes). Unlike I(Kr), the role of the slow component of the delayed rectifier potassium current (I(Ks)) becomes significant only at faster heart rate. Therefore selective blockers of I(Ks) could prolong APD with a reduced propensity to cause pro-arrhythmic side effects. This report describes structure-activity relationships (SARs) of a series of I(Ks) inhibitors derived from 6-alkoxytetralones with good in vitro activity (IC(50) > or =30 nM) and up to 40-fold I(Ks)/I(Kr) selectivity.
Asunto(s)
Amino Alcoholes/farmacología , Bloqueadores de los Canales de Potasio/farmacología , Canales de Potasio con Entrada de Voltaje , Canales de Potasio/fisiología , Tetrahidronaftalenos/farmacología , Amino Alcoholes/química , Animales , Canales de Potasio de Tipo Rectificador Tardío , Cobayas , Cetonas/química , Cetonas/farmacología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/fisiología , Bloqueadores de los Canales de Potasio/química , Tetrahidronaftalenos/químicaRESUMEN
Novel pyrazolopyridopyridazine derivatives have been prepared as potent and selective PDE5 inhibitors. Compound 6 has been identified as a more potent and selective PDE5 inhibitor than sildenafil (1). It is as efficacious as sildenafil in in vitro and in vivo PDE5 inhibition models, and it is orally bioavailable in rats and dogs. The superior isozyme selectivity of 6 is expected to exert less adverse effects in humans when used for erectile dysfunction treatment.
