RESUMEN
A novel series of antagonists of the human A(2A) receptor have been identified and have been shown to display good potency and high degrees of selectivity over other receptor sub-types. Displaying in vivo potency in commonly used disease models and high oral bio-availability, this class of compounds may serve as clinically useful treatments for the relief of the symptoms associated with Parkinson's disease.
Asunto(s)
Antagonistas del Receptor de Adenosina A2 , Amidas/síntesis química , Pirimidinas/química , Administración Oral , Amidas/administración & dosificación , Amidas/química , Animales , Modelos Animales de Enfermedad , Humanos , Ratones , Receptor de Adenosina A2A/metabolismoRESUMEN
Antagonists of the human A(2A) receptor have been reported to have potential therapeutic benefit in the alleviation of the symptoms associated with neurodegenerative movement disorders such as Parkinson's disease. As part of our efforts to discover potent and selective antagonists of this receptor, we herein describe the detailed optimization and structure-activity relationships of a series of pyrimidine-4-carboxamides. These optimized derivatives display desirable physiochemical and pharmacokinetic profiles, which have led to promising oral activity in clinically relevant models of Parkinson's disease.
Asunto(s)
Antagonistas del Receptor de Adenosina A2 , Enfermedad de Parkinson/tratamiento farmacológico , Pirimidinas/química , Pirimidinas/farmacología , Receptor de Adenosina A2A/metabolismo , Animales , Humanos , Locomoción/efectos de los fármacos , Ratones , Unión Proteica , Pirimidinas/farmacocinética , Pirimidinas/uso terapéutico , Relación Estructura-ActividadRESUMEN
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
A series of pyrazolo[3,4-d]pyrimidine, pyrrolo[2,3-d]pyrimidine and 6-arylpurine adenosine A(2A) antagonists is described. Many examples were highly selective against the human A(1) receptor sub-type and were active in an in vivo model of Parkinson's disease.
Asunto(s)
Antagonistas del Receptor de Adenosina A2 , Antiparkinsonianos/uso terapéutico , Diseño de Fármacos , Trastornos Parkinsonianos/tratamiento farmacológico , Purinas/uso terapéutico , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Antagonistas del Receptor de Adenosina A1 , Antiparkinsonianos/síntesis química , Humanos , Modelos Químicos , Purinas/síntesis química , Pirazoles/síntesis química , 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.
Asunto(s)
Antagonistas del Receptor de Adenosina A2 , Antimaláricos/uso terapéutico , Antiparkinsonianos/uso terapéutico , Trastornos Parkinsonianos/tratamiento farmacológico , Pirimidinas/uso terapéutico , Antimaláricos/síntesis química , Antiparkinsonianos/síntesis química , Humanos , Modelos Químicos , Pirimidinas/síntesis química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Antagonistas del Receptor de Adenosina A2 , Azoles/síntesis química , Azoles/farmacología , Diseño de Fármacos , Pirimidinas/síntesis química , Pirimidinas/farmacología , Aminas/química , Animales , Azoles/química , Azoles/uso terapéutico , Evaluación Preclínica de Medicamentos , Trastornos Neurológicos de la Marcha/inducido químicamente , Trastornos Neurológicos de la Marcha/tratamiento farmacológico , Haloperidol/farmacología , Humanos , Ratones , Estructura Molecular , Pirimidinas/química , Pirimidinas/uso terapéutico , Ratas , Receptor de Adenosina A2A/clasificación , Receptor de Adenosina A2A/metabolismo , Relación Estructura-ActividadRESUMEN
Water soluble prodrugs of hybrid free radical scavenger/iron chelating molecules, based on 3,5-disubstituted-4-hydroxyphenyl derivatives and 3-hydroxy-2-methyl-4(1H)-pyridinone (deferiprone), have been prepared. Related hybrid molecules containing a covalent poly(ethylene)glycol or an amine linker were also synthesized.