RESUMO
A series of potent and receptor-selective cannabinoid-1 (CB1) receptor inverse agonists has been discovered. Peripheral selectivity of the compounds was assessed by a mouse tissue distribution study, in which the concentrations of a test compound in both plasma and brain were measured. A number of peripherally selective compounds have been identified through this process. Compound 2p was further evaluated in a 3-week efficacy study in the diet-induced obesity (DIO) mouse model. Beneficial effects on plasma glucose were observed from the compound-treated mice.
Assuntos
Agonismo Inverso de Drogas , Indazóis/farmacologia , Receptor CB1 de Canabinoide/agonistas , Animais , Indazóis/química , Indazóis/farmacocinética , Camundongos , Receptor CB2 de Canabinoide/agonistasRESUMO
A series of benzothiophene-based phosphonates was synthesized and many analogs within the series were shown to be potent antagonists of the TRPM8 channel. The compounds were obtained as a racemic mixture in 5 synthetic steps, and were tested for TRPM8 antagonist activity in a recombinant, canine TRPM8-expressing cell line using a fluorometric imaging plate reader (FLIPR) assay. Structure-activity relationships were developed initially by modification of the core structure and subsequently by variation of the aromatic substituents and the phosphonate ester. Compound 9l was administered intraperitoneally to rats and demonstrated engagement of the TRPM8 target in both prevention and reversal-modes in an icilin-induced 'wet-dog' shake model.
Assuntos
Desenho de Fármacos , Organofosfonatos/síntese química , Canais de Cátion TRPM/antagonistas & inibidores , Animais , Linhagem Celular , Cromatografia Líquida de Alta Pressão , Cães , Concentração Inibidora 50 , Estrutura Molecular , Organofosfonatos/química , Organofosfonatos/farmacologia , Ligação Proteica/efeitos dos fármacos , Ratos , Relação Estrutura-AtividadeRESUMO
High throughput screening of our compound library revealed a series of N-pyridyl-3-benzamides as low micromolar agonists of the human TRPV1 receptor. Synthesis of analogs in this series led to the discovery of a series of N-quinolin-3-yl-benzamides as low nanomolar antagonists of human TRPV1.
Assuntos
Benzamidas/síntese química , Benzamidas/farmacologia , Isoquinolinas/química , Piridinas/química , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/metabolismo , Animais , Benzamidas/química , Benzamidas/uso terapêutico , Reagentes de Ligações Cruzadas/química , Humanos , Hiperalgesia/tratamento farmacológico , Estrutura Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
The unexpected observation of a hyperglycemic effect of some tricycle-based delta opioid receptor (DOR) agonists led to a series of studies to better understand the finding. Single administration of two novel tricyclic DOR agonists dose dependently elevated rat plasma glucose levels; 4-week toxicology studies confirmed the hyperglycemic finding and further revealed pancreatic ß-cell hypertrophy, including vacuole formation, as well as bone dysplasia and Harderian gland degeneration with regeneration. Similar diabetogenic effects were observed in dog. A review of the literature on the antiserotonergic and antihistaminergic drug cyproheptadine (CPH) and its metabolites revealed shared structural features as well as similar hyperglycemic effects to the present series of DOR agonists. To further evaluate these effects, we established an assay measuring insulin levels in the rat pancreatic ß-cell-derived RINm5F cell line, extensively used to study CPH and its metabolites. Like CPH, the initial DOR agonists studied reduced RINm5F cell insulin levels in a concentration-dependent manner. Importantly, compound DOR potency did not correlate with the insulin-reducing potency. Furthermore, the RINm5F cell insulin results correlated with the diabetogenic effect of the compounds in a 5-day mouse study. The RINm5F cell insulin assay enabled the identification of aryl-aryl-amine DOR agonists that lacked an insulin-reducing effect and did not elevate blood glucose in repeated dosing studies conducted over a suprapharmacologic dose range. Thus, not only did the RINm5F cell assay open a path for the further discovery of DOR agonists lacking diabetogenic potential but also it established a reliable, economical, and high-throughput screen for such potential, regardless of chemotype or target pharmacology. The present findings also suggest a mechanistic link between the toxicity observed here and that underlying Wolcott-Rallison Syndrome.
Assuntos
Ciproeptadina/toxicidade , Hiperglicemia/induzido quimicamente , Células Secretoras de Insulina/efeitos dos fármacos , Antagonistas de Entorpecentes/toxicidade , Pâncreas/efeitos dos fármacos , Antagonistas da Serotonina/toxicidade , Animais , Glicemia/análise , Glicemia/efeitos dos fármacos , Crescimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Ciproeptadina/análogos & derivados , Diabetes Mellitus Tipo 1/metabolismo , Cães , Epífises/anormalidades , Epífises/metabolismo , Feminino , Ensaios de Triagem em Larga Escala , Hiperglicemia/metabolismo , Insulina/sangue , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Insulinoma/tratamento farmacológico , Insulinoma/metabolismo , Masculino , Camundongos , Osteocondrodisplasias/metabolismo , Pâncreas/metabolismo , Pâncreas/patologia , Ratos , Ratos Sprague-Dawley , Vacúolos/efeitos dos fármacos , Vacúolos/ultraestruturaRESUMO
We report on a series of alpha-substituted-beta-tetralin-derived and related phenethyl-based isoquinolinyl and hydroxynaphthyl ureas as potent antagonists of the human TRPV1 receptor. The synthesis and Structure-activity relationships (SAR) of the series are described.
Assuntos
Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/metabolismo , Tetra-Hidronaftalenos/farmacologia , Ureia/farmacologia , Ligação Competitiva/efeitos dos fármacos , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Canais de Cátion TRPV/química , Tetra-Hidronaftalenos/química , Ureia/análogos & derivados , Ureia/químicaRESUMO
Starting from a low micromolar agonist lead identified by high-throughput screening, series of N-isoquinolin-5-yl-N'-aralkyl ureas and analogous amides were developed as potent antagonists of human vanilloid receptor 1 (VR1). The synthesis and structure-activity relationships (SAR) of the series are described.