RESUMO
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
A series of N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines, mu opioid receptor antagonists, analogs of alvimopan, were prepared using solid phase methodology. This study led to the identification of a highly selective mu opioid receptor antagonist, which interacts selectively with mu peripheral receptors.
Assuntos
Sistema Nervoso Central/efeitos dos fármacos , Piperidinas/química , Piperidinas/farmacologia , Receptores Opioides delta/antagonistas & inibidores , Receptores Opioides kappa/antagonistas & inibidores , Receptores Opioides mu/antagonistas & inibidores , Administração Oral , Animais , Membrana Celular/metabolismo , Cromatografia Líquida de Alta Pressão , Diprenorfina/metabolismo , Trânsito Gastrointestinal/efeitos dos fármacos , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Humanos , Loperamida/farmacologia , Camundongos , Estrutura Molecular , Piperidinas/síntese química , Receptores Opioides delta/metabolismo , Receptores Opioides kappa/metabolismo , Receptores Opioides mu/metabolismo , Relação Estrutura-AtividadeRESUMO
Chiral recognition and resolution of methanobenzazocines was investigated by HPLC using polysaccharide, Pirkle-type, native and derivatized beta-cyclodextrin chiral stationary phases. Enantioseparation of phenyl substituted 2,6-methanobenzazocines was achieved with multiple chiral stationary phases throughout the classes described. Chiral resolution of the enantiomers of 1,5-methano-3-methyl-6-oxo-1,2,3,4,5,6-hexahydro-3-benzazocine was produced on both polysaccharide and Pirkle-type phases. In the case of 1,5-methano-3-methyl-6-phenyl-1,2,3,4,5,6-hexahydro-3-benzazocine only a dinitrophenyl substituted beta-cyclodextrin produced a separation of enantiomers.
Assuntos
Benzomorfanos/química , Cromatografia Líquida de Alta Pressão/métodos , EstereoisomerismoRESUMO
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
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.
Assuntos
Analgésicos/administração & dosagem , Benzamidas/administração & dosagem , Benzopiranos/administração & dosagem , Dor/tratamento farmacológico , Receptores Opioides delta/agonistas , Administração Oral , Analgésicos/síntese química , Analgésicos/química , Animais , Benzamidas/síntese química , Benzamidas/química , Benzopiranos/síntese química , Benzopiranos/química , Disponibilidade Biológica , Cães , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos , Humanos , Dose Máxima Tolerável , Camundongos , Estrutura Molecular , Atividade Motora/efeitos dos fármacos , Medição da Dor/efeitos dos fármacos , Ratos , Testes de ToxicidadeRESUMO
The microwave-assisted solid-phase synthesis of piperazines, 3,9-diazaspiro[5.5]undecanes and 2,9-diazaspiro[5.5]undecanes is reported. The synthesis relies on the direct annulation of primary amines with resin-bound bismesylates. Critical to the success of this chemistry was the development of alpha-methyl benzyl carbamate resin linker. This resin permits the cleavage of the heterocycles under mildly acidic conditions, free of contaminating linker-derived N-alkylated byproducts.