RESUMEN
We describe here our attempts to optimise the human fatty acid amide hydrolase (FAAH) inhibition and physicochemical properties of our previously reported tetrasubstituted azetidine urea FAAH inhibitor, VER-156084. We describe the SAR of a series of analogues and conclude with the demonstration of in vivo dose-dependant FAAH inhibition in an anandamide-loading study in rats.
Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Azetidinas/farmacología , Inhibidores Enzimáticos/farmacología , Urea/farmacología , Amidohidrolasas/metabolismo , Animales , Azetidinas/síntesis química , Azetidinas/química , Inhibidores Enzimáticos del Citocromo P-450 , Sistema Enzimático del Citocromo P-450/metabolismo , Relación Dosis-Respuesta a Droga , Canal de Potasio ERG1 , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Humanos , Modelos Moleculares , Estructura Molecular , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Urea/síntesis química , Urea/químicaRESUMEN
We report the discovery of a novel, chiral azetidine urea inhibitor of Fatty Acid Amide Hydrolase (FAAH,) and describe the surprising species selectivity of VER-156084 versus rat and human FAAH and also hCB1.
Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Amidohidrolasas/química , Azetidinas/química , Azetidinas/síntesis química , Inhibidores Enzimáticos/síntesis química , Piperidinas/síntesis química , Urea/química , Animales , Azetidinas/farmacología , Catálisis , Química Farmacéutica/métodos , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Humanos , Ratones , Ratones Noqueados , Modelos Químicos , Piperidinas/farmacología , Ratas , Receptor Cannabinoide CB1/química , EstereoisomerismoRESUMEN
We herein report the discovery of a novel class of antagonists of the human adenosine A2B receptor. This low molecular weight scaffold has been optimized to offer derivatives with potential utility for the alleviation of conditions associated with this receptor subtype, such as nociception, diabetes, asthma and COPD. Furthermore, preliminary pharmacokinetic analysis has revealed compounds with profiles suitable for either inhaled or systemic routes of administration.
Asunto(s)
Antagonistas del Receptor de Adenosina A2 , Pirimidinas/química , Administración por Inhalación , Animales , Asma/tratamiento farmacológico , Diseño de Fármacos , Humanos , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Pirimidinas/síntesis química , Pirimidinas/farmacocinética , Ratas , Receptor de Adenosina A2A/metabolismo , Receptor de Adenosina A2B/metabolismoRESUMEN
Antagonism of the human A(2A) receptor has been implicated as a point of therapeutic intervention in the alleviation of the symptoms associated with Parkinson's disease. This is thought to occur, at least in part, by increasing the sensitivity of the dopaminergic neurons to the residual, depleted levels of striatal dopamine. We herein describe a novel series of functionalized triazolo[4,5-d]pyrimidine derivatives that display functional antagonism of the A(2A) receptor. Optimization of these compounds has resulted in improvements in potency, selectivity, and the pharmacokinetic properties of key derivatives. These efforts have led to the discovery of 60 (V2006/BIIB014), which demonstrates strong oral activity in commonly used models of Parkinson's disease. Furthermore, this derivative has shown excellent preclinical pharmacokinetics and has successfully completed phase I clinical studies. This compound is presently undergoing further clinical evaluation in collaboration with Biogen Idec.