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
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
The pharmaceutical industry, particularly the small molecule domain, faces unprecedented challenges of escalating costs, high attrition as well as increasing competitive pressure from other companies and from new treatment modes such as biological products. In other industries, process improvement approaches, such as Lean Sigma, have delivered benefits in speed, quality and cost of delivery. Examining the medicinal chemistry contributions to the iterative improvement process of design-make-test-analyse from a Lean Sigma perspective revealed that major improvements could be made. Thus, the cycle times of synthesis, as well as compound analysis and purification, were reduced dramatically. Improvements focused on team, rather than individual, performance. These new ways of working have consequences for staff engagement, goals, rewards and motivation, which are also discussed.
