RESUMO
A lead optimization campaign in our previously reported sulfamoyl benzamide class of CB(2) agonists was conducted to improve the in vitro metabolic stability profile in this series while retaining high potency and selectivity for the CB(2) receptor. From this study, compound 14, N-(3,4-dimethyl-5-(morpholinosulfonyl)phenyl)-2,2-dimethylbutanamide, was identified as a potent and selective CB(2) agonist exhibiting moderate in vitro metabolic stability and oral bioavailability. Compound 14 demonstrated in vivo efficacy in a rat model of post-surgical pain.
Assuntos
Compostos de Anilina/química , Benzamidas/química , Receptor CB2 de Canabinoide/agonistas , Sulfonamidas/química , Compostos de Anilina/síntese química , Compostos de Anilina/farmacocinética , Animais , Benzamidas/síntese química , Benzamidas/farmacocinética , Humanos , Microssomos Hepáticos/metabolismo , Dor/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Receptor CB2 de Canabinoide/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/farmacocinéticaRESUMO
Selective, nonpeptidic delta opioid receptor agonists have been the subject of great interest as potential novel analgesic agents. The discoveries of BW373U86 (1) and SNC80 (2) contributed to the rapid expansion of research in this field. However, poor drug-like properties and low therapeutic indices have prevented clinical evaluation of these agents. Doses of 1 and 2 similar to those required for analgesic activity produce convulsions in rodents and nonhuman primates. Recently, we described a novel series of potent, selective, and orally bioavailable delta opioid receptor agonists. The lead derivative, ADL5859 (4), is currently in phase II proof-of-concept studies for the management of pain. Further structure activity relationship exploration has led to the discovery of ADL5747 (36), which is approximately 50-fold more potent than 4 in an animal model of inflammatory pain. On the basis of its favorable efficacy, safety, and pharmacokinetic profile, 36 was selected as a clinical candidate for the treatment of pain.
Assuntos
Analgésicos/farmacologia , Analgésicos/uso terapêutico , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Benzopiranos/farmacologia , Benzopiranos/uso terapêutico , Dor/tratamento farmacológico , Receptores Opioides delta/agonistas , Compostos de Espiro/farmacologia , Compostos de Espiro/uso terapêutico , Analgésicos/administração & dosagem , Analgésicos/química , Animais , Benzamidas/administração & dosagem , Benzamidas/química , Benzopiranos/administração & dosagem , Benzopiranos/química , Células CHO , Ensaios Clínicos como Assunto , Cricetinae , Cricetulus , Cristalografia por Raios X , Inibidores do Citocromo P-450 CYP2D6 , Cães , Relação Dose-Resposta a Droga , Descoberta de Drogas , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Humanos , Hiperalgesia/tratamento farmacológico , Masculino , Ratos , Ratos Sprague-Dawley , Compostos de Espiro/administração & dosagem , Compostos de Espiro/químicaRESUMO
Recently sulfamoyl benzamides were identified as a novel series of cannabinoid receptor ligands. Replacing the sulfonamide functionality and reversing the original carboxamide bond led to the discovery of N-(3-(morpholinomethyl)-phenyl)-amides as potent and selective CB(2) agonists. Selective CB(2) agonist 31 (K(i)=2.7; CB(1)/CB(2)=190) displayed robust activity in a rodent model of postoperative pain.
Assuntos
Anti-Inflamatórios/química , Benzamidas/química , Receptor CB2 de Canabinoide/agonistas , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Benzamidas/síntese química , Benzamidas/farmacologia , Células CHO , Linhagem Celular , Cricetinae , Cricetulus , Descoberta de Drogas , Humanos , Dor Pós-Operatória/tratamento farmacológico , Ratos , Receptor CB2 de Canabinoide/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , TransfecçãoRESUMO
Previous research within our laboratories identified sulfamoyl benzamides as novel cannabinoid receptor ligands. Optimization of the amide linkage led to the reverse amide 40. The compound exhibited robust antiallodynic activity in a rodent pain model when administered intraperitoneally. Efficacy after oral administration was observed only when ABT, a cytochrome P450 suicide inhibitor, was coadministered.
Assuntos
Benzamidas/farmacologia , Receptor CB2 de Canabinoide/efeitos dos fármacos , Animais , Benzamidas/administração & dosagem , Benzamidas/química , Benzamidas/uso terapêutico , Dor/tratamento farmacológico , RoedoresRESUMO
Selective delta opioid receptor agonists are promising potential therapeutic agents for the treatment of various types of pain conditions. A spirocyclic derivative was identified as a promising hit through screening. Subsequent lead optimization identified compound 20 (ADL5859) as a potent, selective, and orally bioavailable delta agonist. Compound 20 was selected as a clinical candidate for the treatment of pain.