RESUMEN
Rogaratinib (BAY 1163877) is a highly potent and selective small-molecule pan-fibroblast growth factor receptor (FGFR) inhibitor (FGFR1-4) for oral application currently being investigated in phaseâ 1 clinical trials for the treatment of cancer. In this publication, we report its discovery by deâ novo structure-based design and medicinal chemistry optimization together with its pharmacokinetic profile.
Asunto(s)
Descubrimiento de Drogas , Piperazinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Pirroles/farmacología , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/farmacología , Tiofenos/farmacología , Humanos , Modelos Moleculares , Estructura Molecular , Piperazinas/química , Inhibidores de Proteínas Quinasas/química , Pirroles/química , Bibliotecas de Moléculas Pequeñas/química , Tiofenos/químicaRESUMEN
Adenosine is known to be released under a variety of physiological and pathophysiological conditions to facilitate the protection and regeneration of injured ischemic tissues. The activation of myocardial adenosineâ A1 receptors (A1 Rs) has been shown to inhibit myocardial pathologies associated with ischemia and reperfusion injury, suggesting several options for new cardiovascular therapies. When full A1 R agonists are used, the desired protective and regenerative cardiovascular effects are usually overshadowed by unintended pharmacological effects such as induction of bradycardia, atrioventricular (AV) blocks, and sedation. These unwanted effects can be overcome by using partial A1 R agonists. Starting from previously reported capadenoson we evaluated options to tailor A1 R agonists to a specific partiality range, thereby optimizing the therapeutic window. This led to the identification of the potent and selective agonist neladenoson, which shows the desired partial response on the A1 R, resulting in cardioprotection without sedative effects or cardiac AV blocks. To circumvent solubility and formulation issues for neladenoson, a prodrug approach was pursued. The dipeptide ester neladenoson bialanate hydrochloride showed significantly improved solubility and exposure after oral administration. Neladenoson bialanate hydrochloride is currently being evaluated in clinical trials for the treatment of heart failure.