RESUMEN
Therapeutic interventions are being developed for Huntington's disease (HD), a hallmark of which is mutant huntingtin protein (mHTT) aggregates. Following the advancement to human testing of two [11C]-PET ligands for aggregated mHTT, attributes for further optimization were identified. We replaced the pyridazinone ring of CHDI-180 with a pyrimidine ring and minimized off-target binding using brain homogenate derived from Alzheimer's disease patients. The major in vivo metabolic pathway via aldehyde oxidase was blocked with a 2-methyl group on the pyrimidine ring. A strategically placed ring-nitrogen on the benzoxazole core ensured high free fraction in the brain without introducing efflux. Replacing a methoxy pendant with a fluoro-ethoxy group and introducing deuterium atoms suppressed oxidative defluorination and accumulation of [18F]-signal in bones. The resulting PET ligand, CHDI-650, shows a rapid brain uptake and washout profile in non-human primates and is now being advanced to human testing.
Asunto(s)
Enfermedad de Huntington , Tomografía de Emisión de Positrones , Animales , Humanos , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Ligandos , Tomografía de Emisión de Positrones/métodos , Enfermedad de Huntington/diagnóstico por imagen , Enfermedad de Huntington/tratamiento farmacológico , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismoRESUMEN
We describe herein the discovery and development of a series of 4-arylthieno[3,2-d]pyrimidines which are potent adenosine A(2A) receptor antagonists. These novel compounds show high degrees of selectivity against the human A(1), A(2B) and A(3) receptor sub-types. Moreover, a number of these compounds show promising activity in vivo, suggesting potential utility in the treatment of Parkinson's disease.
Asunto(s)
Antagonistas del Receptor de Adenosina A2 , Antiparkinsonianos/uso terapéutico , Diseño de Fármacos , Trastornos Parkinsonianos/tratamiento farmacológico , Pirimidinas/uso terapéutico , Antagonistas del Receptor de Adenosina A1 , Antagonistas del Receptor de Adenosina A3 , Antiparkinsonianos/síntesis química , Humanos , Modelos Químicos , Pirimidinas/síntesis química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The (-)-(11R,2'S)-enantiomer of the antimalarial drug mefloquine has been found to be a reasonably potent and moderately selective adenosine A(2A) receptor antagonist. Further investigation of this compound has led to the discovery of a series of keto-aryl thieno[3,2-d]pyrimidine derivatives, which are potent and selective antagonists of the adenosine A(2A) receptor. These derivatives show selectivity against the A(1) receptor. Furthermore, some of these compounds have been shown to have in vivo activity in a commonly used model, suggesting the potential for the treatment of Parkinson's disease.