RESUMO
The design and synthesis of novel 1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalen-4-carboxamide CB2 selective ligands for the potential treatment of pain is described. Compound (R,R)-25 has good balance between CB2 agonist potency and selectivity over CB1, and possesses overall favorable pharmaceutical properties. It also demonstrated robust in vivo efficacy mediated via CB2 activation in the rodent models of inflammatory and osteoarthritis pain after oral administration.
Assuntos
Analgésicos não Narcóticos/farmacologia , Compostos Heterocíclicos com 3 Anéis/farmacologia , Inflamação/tratamento farmacológico , Microssomos Hepáticos/efeitos dos fármacos , Osteoartrite/tratamento farmacológico , Dor/tratamento farmacológico , Pirazóis/farmacologia , Receptor CB2 de Canabinoide/agonistas , Administração Oral , Analgésicos não Narcóticos/administração & dosagem , Analgésicos não Narcóticos/química , Animais , Artrite Experimental/tratamento farmacológico , Artrite Experimental/metabolismo , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/química , Humanos , Inflamação/metabolismo , Masculino , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Estrutura Molecular , Osteoartrite/metabolismo , Dor/metabolismo , Pirazóis/administração & dosagem , Pirazóis/química , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Receptor CB1 de Canabinoide/agonistas , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A series of fused bicyclic heterocycles was identified as potent and selective 5-HT(2A) receptor antagonists. Optimization of the series resulted in compounds that had improved PK properties, favorable CNS partitioning, good pharmacokinetic properties, and significant improvements on deep sleep (delta power) and sleep consolidation.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Receptor 5-HT2A de Serotonina/metabolismo , Antagonistas do Receptor 5-HT2 de Serotonina/química , Antagonistas do Receptor 5-HT2 de Serotonina/uso terapêutico , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Sono/efeitos dos fármacos , Animais , Humanos , Ratos , Antagonistas do Receptor 5-HT2 de Serotonina/farmacocinética , Relação Estrutura-AtividadeRESUMO
Potent 5-HT(2A) inverse-agonists containing phenyl-pyrazole ureas with an amino side chain were identified. Optimization of this series resulted in selective compounds that proved effective in modulating 5HT-induced amplification of ADP-stimulated human platelet aggregation.
Assuntos
Inibidores da Agregação Plaquetária/química , Inibidores da Agregação Plaquetária/farmacologia , Agonistas do Receptor 5-HT2 de Serotonina , Ureia/análogos & derivados , Ureia/farmacologia , Humanos , Agregação Plaquetária/efeitos dos fármacos , Pirazóis/química , Pirazóis/farmacologia , Receptor 5-HT2A de Serotonina/metabolismo , Relação Estrutura-AtividadeRESUMO
Recent developments in sleep research suggest that antagonism of the serotonin 5-HT(2A) receptor may improve sleep maintenance insomnia. We herein report the discovery of a series of potent and selective serotonin 5-HT(2A) receptor antagonists based on a phenethylpiperazine amide core structure. When tested in a rat sleep pharmacology model, these compounds increased both sleep consolidation and deep sleep. Within this series of compounds, an improvement in the metabolic stability of early leads was achieved by introducing a carbonyl group into the phenethylpiperazine linker. Of note, compounds 14 and 27 exhibited potent 5-HT(2A) receptor binding affinity, high selectivity over the 5-HT(2C) receptor, favorable CNS partitioning, and good pharmacokinetic and early safety profiles. In vivo, these two compounds showed dose-dependent, statistically significant improvements on deep sleep (delta power) and sleep consolidation at doses as low as 0.1 mg/kg.
Assuntos
Amidas/síntese química , Piperazinas/síntese química , Pirazóis/síntese química , Antagonistas do Receptor 5-HT2 de Serotonina , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Sono/efeitos dos fármacos , Administração Oral , Amidas/farmacocinética , Amidas/farmacologia , Animais , Disponibilidade Biológica , Proteínas Sanguíneas/metabolismo , Encéfalo/metabolismo , Cães , Agonismo Inverso de Drogas , Haplorrinos , Humanos , Masculino , Microssomos Hepáticos/metabolismo , Piperazinas/farmacocinética , Piperazinas/farmacologia , Ligação Proteica , Pirazóis/farmacocinética , Pirazóis/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
Serotonin, which is stored in platelets and is released during thrombosis, activates platelets via the 5-HT(2A) receptor. 5-HT(2A) receptor inverse agonists thus represent a potential new class of antithrombotic agents. Our medicinal program began with known compounds that displayed binding affinity for the recombinant 5-HT(2A) receptor, but which had poor activity when tested in human plasma platelet inhibition assays. We herein describe a series of phenyl pyrazole inverse agonists optimized for selectivity, aqueous solubility, antiplatelet activity, low hERG activity, and good pharmacokinetic properties, resulting in the discovery of 10k (APD791). 10k inhibited serotonin-amplified human platelet aggregation with an IC(50) = 8.7 nM and had negligible binding affinity for the closely related 5-HT(2B) and 5-HT(2C) receptors. 10k was orally bioavailable in rats, dogs, and monkeys and had an acceptable safety profile. As a result, 10k was selected further evaluation and advanced into clinical development as a potential treatment for arterial thrombosis.
Assuntos
Artérias/efeitos dos fármacos , Benzamidas/química , Benzamidas/farmacologia , Descoberta de Drogas/métodos , Agonismo Inverso de Drogas , Morfolinas/química , Morfolinas/farmacologia , Pirazóis/química , Pirazóis/farmacologia , Agonistas do Receptor 5-HT2 de Serotonina , Trombose/tratamento farmacológico , Animais , Benzamidas/metabolismo , Benzamidas/farmacocinética , Cães , Feminino , Humanos , Concentração Inibidora 50 , Masculino , Morfolinas/metabolismo , Morfolinas/farmacocinética , Agregação Plaquetária/efeitos dos fármacos , Pirazóis/metabolismo , Pirazóis/farmacocinética , Ratos , Receptor 5-HT2A de Serotonina/metabolismo , Relação Estrutura-Atividade , Especificidade por Substrato , Trombose/metabolismoRESUMO
Insomnia affects a growing portion of the adult population in the U.S. Most current therapeutic approaches to insomnia primarily address sleep onset latency. Through the 5-hydroxytryptamine(2A) (5-HT(2A)) receptor, serotonin (5-HT) plays a role in the regulation of sleep architecture, and antagonists/inverse-agonists of 5-HT(2A) have been shown to enhance slow wave sleep (SWS). We describe here a series of 5-HT(2A) inverse-agonists that when dosed in rats, both consolidate the stages of NREM sleep, resulting in fewer awakenings, and increase a physiological measure of sleep intensity. These studies resulted in the discovery of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl]-3-(2,4-difluorophenyl)urea (Nelotanserin), a potent inverse-agonist of 5-HT(2A) that was advanced into clinical trials for the treatment of insomnia.