RESUMO
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.
Assuntos
Antagonistas do Receptor A2 de Adenosina , Doença de Parkinson/tratamento farmacológico , Pirimidinas/química , Pirimidinas/farmacologia , Receptor A2A de Adenosina/metabolismo , Animais , Humanos , Locomoção/efeitos dos fármacos , Camundongos , Ligação Proteica , Pirimidinas/farmacocinética , Pirimidinas/uso terapêutico , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Antagonistas do Receptor A2 de Adenosina , Antiparkinsonianos/uso terapêutico , Desenho de Fármacos , Transtornos Parkinsonianos/tratamento farmacológico , Pirimidinas/uso terapêutico , Antagonistas do Receptor A1 de Adenosina , Antagonistas do Receptor A3 de Adenosina , Antiparkinsonianos/síntese química , Humanos , Modelos Químicos , Pirimidinas/síntese química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A series of analogues of the peptide deformylase (PDF) inhibitor BB-3497 where the P3' amide bond was replaced with a ketone functionality is described. The in vitro antibacterial profiling of these compounds revealed that they demonstrate activity against pathogens associated with respiratory tract infections.
Assuntos
Amidoidrolases/antagonistas & inibidores , Anti-Infecciosos/química , Inibidores Enzimáticos/química , Infecções Respiratórias/enzimologia , Infecções Respiratórias/microbiologia , Amidoidrolases/metabolismo , Anti-Infecciosos/farmacologia , Anti-Infecciosos/uso terapêutico , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Haemophilus influenzae/efeitos dos fármacos , Haemophilus influenzae/enzimologia , Testes de Sensibilidade Microbiana/estatística & dados numéricos , Moraxella catarrhalis/efeitos dos fármacos , Moraxella catarrhalis/enzimologia , Streptococcus pneumoniae/efeitos dos fármacos , Streptococcus pneumoniae/enzimologiaRESUMO
Structural modifications to the peptide deformylase inhibitor BB-3497 are described. In this paper, we describe the initial SAR around this lead for modifications to the methylene spacer and the P1' side chain. Enzyme inhibition and antibacterial activity data revealed that the optimum distance between the N-formyl hydroxylamine metal binding group and the P1' side chain is one unsubstituted methylene unit. Additionally, lipophilic P1' side chains that closely mimic the methionine residue in the substrate provided compounds with the best microbiological profile.
Assuntos
Amidoidrolases/antagonistas & inibidores , Antibacterianos/síntese química , Ácidos Hidroxâmicos/química , Metano/análogos & derivados , Antibacterianos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Hidrocarbonetos , Ácidos Hidroxâmicos/farmacologia , Hidroxilamina/química , Concentração Inibidora 50 , Metais/química , Metano/química , Testes de Sensibilidade Microbiana , Mimetismo Molecular , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Relação Estrutura-AtividadeRESUMO
A series of analogues of the potent peptide deformylase (PDF) inhibitor BB-3497 containing alternative metal binding groups was synthesised. Enzyme inhibition and antibacterial activity data for these compounds revealed that the bidentate hydroxamic acid and N-formyl hydroxylamine structural motifs represent the optimum chelating groups on the pseudopeptidic BB-3497 backbone.