RESUMO
High throughput screening identified the pyridothienopyrimidinone 1 as a ligand for the metabotropic glutamate receptor 1 (mGluR1=10 nM). Compound 1 has an excellent in vivo profile; however, it displays unfavorable pharmacokinetic issues and metabolic stability. Therefore, using 1 as a template, novel analogues (10i) were prepared. These analogues displayed improved oral exposure and activity in the Spinal Nerve Ligation (SNL) pain model.
Assuntos
Compostos Heterocíclicos com 3 Anéis/química , Pirimidinonas/química , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Tiofenos/química , Administração Oral , Animais , Dor Crônica/tratamento farmacológico , Modelos Animais de Doenças , Compostos Heterocíclicos com 3 Anéis/síntese química , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Humanos , Pirimidinonas/síntese química , Pirimidinonas/uso terapêutico , Ratos , Receptores de Glutamato Metabotrópico/metabolismo , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/uso terapêuticoRESUMO
Novel P2X(7) antagonists were developed using a purine scaffold. These compounds were potent and selective at the P2X(7) receptor in human and rodent as well as efficacious in rodent pain models. Compound 15a was identified to have oral potency in several pain models in rodent similar to naproxen, gabapentin and pregabalin. Structure-activity relationship (SAR) development and results of pain models are presented.
Assuntos
Dor/tratamento farmacológico , Antagonistas do Receptor Purinérgico P2X/síntese química , Purinas/síntese química , Receptores Purinérgicos P2X7/química , Animais , Humanos , Antagonistas do Receptor Purinérgico P2X/química , Antagonistas do Receptor Purinérgico P2X/uso terapêutico , Purinas/química , Purinas/uso terapêutico , Ratos , Receptores Purinérgicos P2X7/metabolismo , Relação Estrutura-AtividadeRESUMO
Structure-activity relationship (SAR) efforts around our initial lead compound 1 led to the identification of potent P2X(7) receptor antagonists with improved pharmacokinetic profiles. These compounds were potent and selective at the P2X(7) receptor in both human and rodent. Compound (entry 31) exhibited oral efficacy in the rat MIA and CCI pain models.
Assuntos
Analgésicos/síntese química , Desenho de Fármacos , Dor , Antagonistas do Receptor Purinérgico P2/síntese química , Administração Oral , Analgésicos/química , Animais , Modelos Animais de Doenças , Humanos , Estrutura Molecular , Dor/tratamento farmacológico , Antagonistas do Receptor Purinérgico P2/química , Ratos , Receptores Purinérgicos P2X7/metabolismo , Relação Estrutura-AtividadeRESUMO
A series of N-8 substituted analogs based upon the spiropiperidine core of the original lead compound 1 was synthesized. This lead has been elaborated to compounds to give compounds 2 and 3 (R=H) that exhibited high NOP binding affinity as well as selectivity against other known opioid receptors. These two series have been further functionalized at the amido nitrogen. The synthesis and structure-activity relationship (SAR) of these and related compounds are discussed.
Assuntos
Piperidinas/síntese química , Piperidinas/farmacologia , Receptores Opioides/efeitos dos fármacos , Compostos de Espiro/síntese química , Compostos de Espiro/farmacologia , Animais , Sítios de Ligação , Capsaicina/farmacologia , Técnicas de Química Combinatória , Tosse/induzido quimicamente , Modelos Animais de Doenças , Desenho de Fármacos , Cobaias , Estrutura Molecular , Piperidinas/química , Receptores Opioides/metabolismo , Compostos de Espiro/química , Relação Estrutura-Atividade , Receptor de NociceptinaRESUMO
A series of N-substituted analogs based upon the spiropiperidine core of 1 was synthesized and exhibited high binding affinity to the nociceptin (NOP) receptor. The selectivities against other known opioid receptors were determined.
Assuntos
Piperidinas/síntese química , Receptores Opioides/agonistas , Administração Oral , Animais , Tosse/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos , Guanosina 5'-O-(3-Tiotrifosfato) , Ligantes , Farmacocinética , Piperidinas/farmacocinética , Piperidinas/farmacologia , Ligação Proteica , Ratos , Receptores Opioides/metabolismo , Compostos de Espiro/síntese química , Compostos de Espiro/farmacocinética , Compostos de Espiro/farmacologia , Relação Estrutura-Atividade , Receptor de NociceptinaRESUMO
A novel series of 3-substituted-8-aryl-[1,2,4]-triazolo[5,1-i]purin-5-amine analogs related to Sch 58261 was synthesized in order to identify potent adenosine A(2A) receptor antagonists with improved selectivity over the A(1) receptor, physiochemical properties, and pharmacokinetic profiles as compared to those of Sch 58261. As a result of structural modifications, numerous analogs with excellent in vitro binding affinities and selectivities were identified. Moreover, compound 27 displayed both superior in vitro and highly promising in vivo profiles.
Assuntos
Antagonistas do Receptor A2 de Adenosina , Fármacos Neuroprotetores/farmacologia , Purinas/síntese química , Purinas/farmacologia , Pirimidinas/farmacologia , Triazóis/síntese química , Triazóis/farmacologia , Antagonistas do Receptor A1 de Adenosina , Fenômenos Químicos , Físico-Química , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Relação Estrutura-AtividadeRESUMO
The structure-activity relationship of this novel class of compounds based on 2-(2-furanyl)-7-phenyl[1,2,4]-triazolo[1,5-c]pyrimidin-5-amine, 1, and its analogs was evaluated for their in vitro and in vivo adenosine A(2A) receptor antagonism. Several compounds displayed oral activity at 3 mg/kg in a rat catalepsy model. Specifically, compound 8g displayed an excellent in vitro profile, as well as a highly promising in vivo profile.
Assuntos
Antagonistas do Receptor A2 de Adenosina , Pirimidinas/farmacologia , Triazóis/farmacologia , Administração Oral , Animais , Catalepsia/tratamento farmacológico , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Masculino , Estrutura Molecular , Pirimidinas/química , Pirimidinas/classificação , Pirimidinas/uso terapêutico , Ratos , Relação Estrutura-Atividade , Triazóis/química , Triazóis/uso terapêuticoRESUMO
The structure-activity relationship (SAR) exploration using 2-(2-furanyl)-7-phenyl[1,2,4]triazolo-[1,5-c]pyrimidin-5-amine (1) as a template led to the identification of a novel class of potent and selective adenosine A2A receptor (AR) antagonists. However, these compounds were found to be associated with significant hERG activity. This report discusses the strategy and outcome of an expanded SAR focused on addressing the hERG liability. As a result, compounds 21 and 24 possess excellent in vitro profiles, highly promising in vivo profiles, and acceptable levels of hERG channel inhibition.
Assuntos
Antagonistas do Receptor A2 de Adenosina , Pirimidinas/farmacologia , Triazóis/farmacologia , Administração Oral , Animais , Catalepsia/tratamento farmacológico , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Estrutura Molecular , Atividade Motora/efeitos dos fármacos , Pirimidinas/química , Pirimidinas/classificação , Pirimidinas/uso terapêutico , Ratos , Relação Estrutura-Atividade , Triazóis/química , Triazóis/uso terapêuticoRESUMO
In high throughput screening of our file compounds, a novel structure 1 was identified as a potent A(2A) receptor antagonist with no selectivity over the A1 adenosine receptor. The structure-activity relationship investigation using 1 as a template lead to identification of a novel class of compounds as potent and selective antagonists of A(2A) adenosine receptor. Compound 26 was identified to be the most potent A(2A) receptor antagonist (Ki = 0.8 nM) with 100-fold selectivity over the A1 adenosine receptor.