RESUMO
Agonists of the cannabinoid receptor 1 (CB1) have been suggested as possible treatments for a range of medical disorders including gastroesophageal reflux disease (GERD). While centrally acting cannabinoid agonists are known to produce psychotropic effects, it has been suggested that the CB1 receptors in the periphery could play a significant role in reducing reflux. A moderately potent and highly lipophilic series of 2-aminobenzamides was identified through focused screening of GPCR libraries. Development of this series focused on improving potency and efficacy at the CB1 receptor, reducing lipophilicity and limiting the central nervous system (CNS) exposure while maintaining good oral absorption. Improvement of the series led to compounds having excellent potency at the CB1 receptor and high levels of agonism, good physical and pharmacokinetic properties, and low penetration into the CNS. A range of compounds demonstrated a dose-dependent inhibition of transient lower esophageal sphincter relaxations in a dog model.
Assuntos
Benzamidas/síntese química , Encéfalo/metabolismo , Refluxo Gastroesofágico/tratamento farmacológico , Receptor CB1 de Canabinoide/agonistas , Administração Oral , Animais , Hidrocarboneto de Aril Hidroxilases/antagonistas & inibidores , Benzamidas/farmacocinética , Benzamidas/farmacologia , Disponibilidade Biológica , Linhagem Celular , Cricetinae , Cricetulus , Citocromo P-450 CYP2C9 , Citocromo P-450 CYP3A , Inibidores do Citocromo P-450 CYP3A , Cães , Canal de Potássio ERG1 , Esfíncter Esofágico Inferior/efeitos dos fármacos , Esfíncter Esofágico Inferior/fisiologia , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Ensaios de Triagem em Larga Escala , Humanos , Relaxamento Muscular/efeitos dos fármacos , Pirazinas/síntese química , Pirazinas/farmacocinética , Pirazinas/farmacologia , Piridinas/síntese química , Piridinas/farmacocinética , Piridinas/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Solubilidade , Relação Estrutura-Atividade , Sulfóxidos/síntese química , Sulfóxidos/farmacocinética , Sulfóxidos/farmacologia , Triazóis/síntese química , Triazóis/farmacocinética , Triazóis/farmacologiaRESUMO
We have previously demonstrated that the prototypical GABA B receptor agonist baclofen inhibits transient lower esophageal sphincter relaxations (TLESRs), the most important mechanism for gastroesophageal reflux. Thus, GABA B agonists could be exploited for the treatment of gastroesophageal reflux disease. However, baclofen, which is used as an antispastic agent, and other previously known GABA B agonists can produce CNS side effects such as sedation, dizziness, nausea, and vomiting at higher doses. We now report the discovery of atypical GABA B agonists devoid of classical GABA B agonist related CNS side effects at therapeutic doses and the optimization of this type of compound for inhibition of TLESRs, which has resulted in a candidate drug ( R)- 7 (AZD3355) that is presently being evaluated in man.