RESUMO
An adenosine A2A receptor antagonist may be useful for the treatment of Parkinson's disease. Synthesis and structure-activity studies starting from 4-(3,3-dimethylbutyrylamino)-3,5-difluoro-N-thiazol-2-yl-benzamide (Lu AA41063, 4) led to a novel series of human (h) A2A receptor antagonists with improved aqueous solubility. Compound 22 was identified as a key representative from the series, displaying submicromolar hA2A receptor affinity and excellent aqueous solubility. Compound 22 also displayed good in vitro pharmacokinetic properties and is considered a good starting point for further lead optimisation toward hA2A receptor antagonists with improved druggability properties.
Assuntos
Antagonistas do Receptor A2 de Adenosina/síntese química , Receptor A2A de Adenosina/química , Tiazóis/síntese química , para-Aminobenzoatos/síntese química , Antagonistas do Receptor A2 de Adenosina/química , Antagonistas do Receptor A2 de Adenosina/metabolismo , Sítios de Ligação , Humanos , Ligantes , Simulação de Acoplamento Molecular , Ligação Proteica , Receptor A2A de Adenosina/metabolismo , Solubilidade , Relação Estrutura-Atividade , Tiazóis/química , Água/química , para-Aminobenzoatos/químicaRESUMO
Sortilin is a type I membrane glycoprotein belonging to the vacuolar protein sorting 10 protein (Vps10p) family of sorting receptors and is most abundantly expressed in the central nervous system. Sortilin has emerged as a key player in the regulation of neuronal viability and has been implicated as a possible therapeutic target in a range of disorders. Here, the identification of AF40431, the first reported small-molecule ligand of sortilin, is reported. Crystals of the sortilin-AF40431 complex were obtained by co-crystallization and the structure of the complex was solved to 2.7â Å resolution. AF40431 is bound in the neurotensin-binding site of sortilin, with the leucine moiety of AF40431 mimicking the binding mode of the C-terminal leucine of neurotensin and the 4-methylumbelliferone moiety of AF40431 forming π-stacking with a phenylalanine.
Assuntos
Proteínas Adaptadoras de Transporte Vesicular/antagonistas & inibidores , Proteínas Adaptadoras de Transporte Vesicular/química , Cumarínicos/química , Leucina/análogos & derivados , Bibliotecas de Moléculas Pequenas/química , Proteínas Adaptadoras de Transporte Vesicular/genética , Sítios de Ligação , Cristalização , Cristalografia por Raios X , Células HEK293 , Humanos , Leucina/química , Ligantes , Neurotensina/química , Fenilalanina/química , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Relação Estrutura-AtividadeRESUMO
The identification of the novel, selective, orally bioavailable Sortilin inhibitor AF38469 is described. Structure-activity relationships and syntheses are reported, along with an X-ray crystal structure of the sortilin-AF38469 protein-inhibitor complex.
Assuntos
Proteínas Adaptadoras de Transporte Vesicular/antagonistas & inibidores , Hidrocarbonetos Fluorados/farmacologia , Piridinas/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Triagem em Larga Escala , Hidrocarbonetos Fluorados/síntese química , Hidrocarbonetos Fluorados/química , Modelos Moleculares , Estrutura Molecular , Piridinas/síntese química , Piridinas/química , Ratos , Relação Estrutura-AtividadeRESUMO
Herein we describe the discovery of a series of novel adenosine A(2A) receptor antagonists. A successful hit-to-lead optimization of an HTS hit led to replacement of a metabolically labile ester moiety with a heteroaromatic group. A compound from the series, (cyclopropanecarboxylic acid [5-(5-methyl-[1,2,4]oxadiazol-3-yl)-4-phenyl-thiazol-2-yl]-amide, compound 13), was shown to be effective in reversing haloperidol-induced hypolocomotion, a model of motor dysfunction in Parkinson's Disease.
