RESUMO
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.
Assuntos
Amidoidrolases/antagonistas & inibidores , Azetidinas/farmacologia , Inibidores Enzimáticos/farmacologia , Ureia/farmacologia , Amidoidrolases/metabolismo , Animais , Azetidinas/síntese química , Azetidinas/química , Inibidores das Enzimas do Citocromo P-450 , Sistema Enzimático do Citocromo P-450/metabolismo , Relação Dose-Resposta a Droga , Canal de Potássio ERG1 , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Humanos , Modelos Moleculares , Estrutura Molecular , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Ureia/síntese química , Ureia/químicaRESUMO
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.
Assuntos
Antagonistas do Receptor A2 de Adenosina , Pirimidinas/química , Administração por Inalação , Animais , Asma/tratamento farmacológico , Desenho de Fármacos , Humanos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Pirimidinas/síntese química , Pirimidinas/farmacocinética , Ratos , Receptor A2A de Adenosina/metabolismo , Receptor A2B de Adenosina/metabolismoRESUMO
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.
Assuntos
Amidoidrolases/antagonistas & inibidores , Amidoidrolases/química , Azetidinas/química , Azetidinas/síntese química , Inibidores Enzimáticos/síntese química , Piperidinas/síntese química , Ureia/química , Animais , Azetidinas/farmacologia , Catálise , Química Farmacêutica/métodos , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Humanos , Camundongos , Camundongos Knockout , Modelos Químicos , Piperidinas/farmacologia , Ratos , Receptor CB1 de Canabinoide/química , EstereoisomerismoRESUMO
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.
