RESUMEN
A series of isoindolinone compounds have been developed showing good in vitro potency on the Kv1.5 ion channel. By modification of two side chains on the isoindolinone scaffold, metabolically stable compounds with good in vivo PK profile could be obtained leaving the core structure unsubstituted. In this way, low microsomal intrinsic clearance (CLint) could be achieved despite a relatively high logD. The compounds were synthesized using the Ugi reaction, in some cases followed by Suzuki and Diels-Alder reactions, giving a diverse set of compounds in a small number of reaction steps.
Asunto(s)
Isoindoles/farmacología , Canal de Potasio Kv1.5/antagonistas & inhibidores , Bloqueadores de los Canales de Potasio/farmacología , Animales , Relación Dosis-Respuesta a Droga , Humanos , Isoindoles/síntesis química , Isoindoles/química , Ratones , Modelos Animales , Estructura Molecular , Bloqueadores de los Canales de Potasio/síntesis química , Bloqueadores de los Canales de Potasio/química , Relación Estructura-ActividadRESUMEN
A series of lactam sulfonamides has been discovered and optimized as inhibitors of the Kv1.5 potassium ion channel for treatment of atrial fibrillation. In vitro structure-activity relationships from lead structure C to optimized structure 3y are described. Compound 3y was evaluated in a rabbit PD-model and was found to selectively prolong the atrial effective refractory period at submicromolar concentrations.
Asunto(s)
Canal de Potasio Kv1.5/antagonistas & inhibidores , Lactamas/química , Bloqueadores de los Canales de Potasio/química , Pirrolidinonas/química , Sulfonamidas/química , Animales , Perros , Semivida , Humanos , Canal de Potasio Kv1.5/metabolismo , Bloqueadores de los Canales de Potasio/síntesis química , Bloqueadores de los Canales de Potasio/farmacocinética , Pirrolidinonas/síntesis química , Pirrolidinonas/farmacocinética , Conejos , Ratas , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/farmacocinéticaRESUMEN
The T-type calcium channel inhibitor Mibefradil was reported to protect the heart from atrial remodeling, a key process involved in the development of atrial fibrillation and arrhythmias. Mibefradil is not a selective T-type calcium channel inhibitor and also affects the function of different ion channels. Our aim was to develop a selective T-type calcium channel inhibitor to validate the importance of T-type-related pharmacology in atrial fibrillation. Structural optimisation of a previously disclosed hit series focussed on minimising exposure to the central nervous system and improving pharmacokinetic properties, while maintain adequate potency and selectivity. This resulted in the design of N-[[1-[2-(tert-butylcarbamoylamino)ethyl]-4-(hydroxymethyl)-4-piperidyl]methyl]-3,5-dichloro-benzamide, a novel, selective, peripherally restricted chemical probe to verify the role of T-type calcium channel inhibition on atrial fibrillation protection.
Asunto(s)
Benzamidas/química , Bloqueadores de los Canales de Calcio/química , Canales de Calcio Tipo T/química , Animales , Benzamidas/síntesis química , Benzamidas/farmacocinética , Bloqueadores de los Canales de Calcio/síntesis química , Bloqueadores de los Canales de Calcio/farmacocinética , Canales de Calcio Tipo T/metabolismo , Perros , Evaluación Preclínica de Medicamentos , Semivida , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Relación Estructura-ActividadRESUMEN
Diphenylphosphinic amides and diphenylphosphine oxides have been synthesized and tested as inhibitors of the Kv1.5 potassium ion channel as a possible treatment for atrial fibrillation. In vitro structure-activity relationships are discussed and several compounds with Kv1.5 IC(50) values of <0.5 µM were discovered. Selectivity over the ventricular IKs current was monitored and selective compounds were found. Results from a rabbit PD-model are included.
Asunto(s)
Amidas/síntesis química , Amidas/farmacología , Canal de Potasio Kv1.5/antagonistas & inhibidores , Óxidos/síntesis química , Óxidos/farmacología , Fosfinas/síntesis química , Fosfinas/farmacología , Amidas/química , Animales , Compuestos de Bifenilo/química , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Óxidos/química , Fosfinas/química , Ácidos Fosfínicos/química , Unión Proteica/efectos de los fármacos , Conejos , Relación Estructura-ActividadRESUMEN
Chemical evolution of a HTS-based fragment hit resulted in the identification of N-(1-adamantyl)-2-[4-(2-tetrahydropyran-4-ylethyl)piperazin-1-yl]acetamide, a novel, selective T-type calcium channel (Ca(v)3.2) inhibitor with in vivo antihypertensive effect in rats.
Asunto(s)
Acetamidas/farmacología , Antihipertensivos/farmacología , Canales de Calcio Tipo T/metabolismo , Descubrimiento de Drogas , Acetamidas/síntesis química , Acetamidas/química , Animales , Antihipertensivos/síntesis química , Antihipertensivos/química , Relación Dosis-Respuesta a Droga , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Canales de Potasio Éter-A-Go-Go/metabolismo , Ensayos Analíticos de Alto Rendimiento , Humanos , Estructura Molecular , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Model-based analysis of routinely generated pharmacokinetic and pharmacodynamic (PK-PD) data is a key component of preclinical drug discovery. The work process of such analyses can be automated by properly designed computer programs that reduce the number of manual steps, resulting in time saving and significantly fewer errors. Critical decisions can still be made by modelers. Using concrete animal data examples this paper illustrates when, and demonstrates how, automated PK-PD approaches can be used and what benefits they offer to the modeling and simulation community. Specifically, we describe two compound optimization case studies from drug discovery projects, and also demonstrate how a subsequent optimization step to predict the human dose can be coupled to an automated approach.
Asunto(s)
Descubrimiento de Drogas/estadística & datos numéricos , Evaluación Preclínica de Medicamentos/estadística & datos numéricos , Modelos Biológicos , Animales , Biología Computacional , Simulación por Computador , Humanos , Farmacocinética , Fenómenos Farmacológicos , Receptores de Droga/efectos de los fármacos , Receptores de Droga/metabolismo , Programas InformáticosRESUMEN
OBJECTIVE: To examine the electrophysiological, hemodynamic, and antiarrhythmic effects of the novel antiarrhythmic agent AZ13395438. METHODS: The ion channel-blocking potency of AZ13395438 was assessed in Chinese hamster ovary cells stably expressing various human cardiac ion channels and in human atrial myocytes. The in vivo electrophysiological, hemodynamic, and antiarrhythmic effects of intravenously administered AZ13395438 were examined in anesthetized rabbits, in anesthetized naive dogs, and in dogs subjected to rapid atrial pacing (RAP) for 8 weeks. Pharmacokinetic/pharmacodynamic (PKPD) modeling was applied to predict the potency of AZ13395438 in increasing atrial and ventricular refractoriness. RESULTS: AZ13395438 potently and predominantly blocked the atrial repolarizing potassium currents I(Kur), I(Ach), and I(to) in vitro. In vivo, AZ13395438 caused a concentration-dependent and selective increase in atrial refractoriness with no or small effects on ventricular refractoriness and repolarization and on hemodynamics in both rabbits and dogs. The PKPD modeling predicted unbound plasma concentrations of AZ13395438 of 0.20 ± 0.039, 0.38 ± 0.084, and 0.34 ± 0.057 µmol/L to increase the right atrial effective refractory period by 20 milliseconds in the rabbit and in the naive and the RAP dogs, respectively. In the RAP dog with atrial fibrillation (AF), AZ13395438 significantly increased AF cycle length and successfully converted AF to sinus rhythm in 12 of the 12 occasions at an unbound plasma concentration of 0.48 ± 0.076 µmol/L. During saline infusion, conversion was seen only in 4 of the 10 occasions (P = .003 vs AZ13395438). Furthermore, AZ13395438 reduced AF inducibility by burst pacing from 100% to 25% (P < .001). CONCLUSION: AZ13395438 can be characterized as a mixed potassium ion channel-blocking agent that selectively prolongs atrial versus ventricular refractoriness and shows promising antiarrhythmic efficacy in a clinically relevant animal model of AF.