RESUMO
JD5037 is a novel peripherally restricted CB1 receptor (CB1R) inverse agonist being developed for the treatment of visceral obesity and its metabolic complications, including nonalcoholic fatty liver disease and dyslipidemia. JD5037 was administered by oral gavage at 10, 40, and 150â¯mg/kg/day dose levels for up to 34 days to Sprague Dawley rats, and at 5, 20, and 75â¯mg/kg/day dose levels for 28 consecutive days to Beagle dogs. In rats, higher incidences of stereotypic behaviors were observed in 10â¯mg/kg females and 40â¯mg/kg males, and slower responses for reflex and sensory tests were observed only in males at 10 and 40â¯mg/kg during neurobehavioral testing. Sporadic minimal incidences of decreased activity (males) and seizures (both sexes) were observed in rats during daily clinical observations, without any clear dose-relationship. Male dogs at 75â¯mg/kg during treatment period, but not recovery period, had an increased incidence of gut associated lymphoid tissue hyperplasia and inflammation in the intestine. In both species, highest dose resulted in lower AUCs indicative of non-linear kinetics. Free access to food increased the plasma AUC∞ by ~4.5-fold at 20â¯mg/kg in dogs, suggesting presence of food may help in systemic absorption of JD5037 in dogs. Based on the study results, 150â¯mg/kg/day in rats, and 20 and 75â¯mg/kg/day doses in male and female dogs, respectively, were determined to be the no-observed-adverse-effect-levels (NOAELs).
Assuntos
Drogas em Investigação/toxicidade , Pirazóis/toxicidade , Receptor CB1 de Canabinoide/agonistas , Convulsões/induzido quimicamente , Comportamento Estereotipado/efeitos dos fármacos , Sulfonamidas/toxicidade , Animais , Área Sob a Curva , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Cães , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Drogas em Investigação/uso terapêutico , Feminino , Humanos , Aplicação de Novas Drogas em Teste , Masculino , Nível de Efeito Adverso não Observado , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Pirazóis/farmacocinética , Pirazóis/uso terapêutico , Ratos , Ratos Sprague-Dawley , Fatores Sexuais , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapêuticoRESUMO
JD5037 (1) is a potent and selective, peripherally acting inverse agonist of the cannabinoid (CB1 R) receptor. Peripheral CB1 receptor antagonists/inverse agonists have great potential in the treatment of metabolic disorders like type 2 diabetes, obesity, and nonalcoholic steatohepatitis. We report the synthesis of octadeuterated [2 H8 ]-JD5037 (S, S) (8) along with its (S, R) diastereomer (13) from commercially available L-valine-d8 starting material. The [2 H8 ]-JD5037 compound will be used to quantitate unlabeled JD5037 during clinical ADME studies and will be used as an LC-MS/MS bioanalytical standard.
Assuntos
Deutério/química , Pirazóis/química , Pirazóis/síntese química , Sulfonamidas/química , Sulfonamidas/síntese química , Amidas/química , Técnicas de Química Sintética , Modelos Moleculares , Conformação Molecular , Pirazóis/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Sulfonamidas/metabolismoRESUMO
Antagonists (inverse agonists) of the cannabinoid-1 (CB1) receptor showed promise as new therapies for controlling obesity and related metabolic function/liver disease. These agents, representing diverse chemical series, shared the property of brain penetration due to the initial belief that therapeutic benefit was mainly based on brain receptor interaction. However, undesirable CNS-based side effects of the only marketed agent in this class, rimonabant, led to its removal, and termination of the development of other clinical candidates soon followed. Re-evaluation of this approach has focused on neutral or peripherally restricted (PR) antagonists. Supporting these strategies, pharmacological evidence indicates most if not all of the properties of globally acting agents may be captured by molecules with little brain presence. Methodology that can be used to eliminate BBB penetration and the means (in vitro assays, tissue distribution and receptor occupancy determinations, behavioral paradigms) to identify potential agents with little brain presence is discussed. Focus will be on the pharmacology supporting the contention that reported agents are truly peripherally restricted. Notable examples of these types of compounds are: TM38837 (structure not disclosed); AM6545 (8); JD5037 (15b); RTI-12 (19).
Assuntos
Descoberta de Drogas/métodos , Hepatopatias/tratamento farmacológico , Doenças Metabólicas/tratamento farmacológico , Obesidade/tratamento farmacológico , Receptor CB1 de Canabinoide/antagonistas & inibidores , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Cocaína/análogos & derivados , Cocaína/química , Cocaína/farmacologia , Cocaína/uso terapêutico , Humanos , Hepatopatias/metabolismo , Doenças Metabólicas/metabolismo , Morfolinas/química , Morfolinas/farmacologia , Morfolinas/uso terapêutico , Obesidade/metabolismo , Piperidinas/química , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Pirazóis/química , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Receptor CB1 de Canabinoide/metabolismo , Rimonabanto , Sulfonamidas/química , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêuticoRESUMO
Analogs of SLV-319 (Ibipinibant), a CB1 receptor inverse agonist, were synthesized with functionality intended to limit brain exposure while maintaining the receptor affinity and selectivity of the parent compound. Structure activity relationships of this series, and pharmacology of two lead compounds, 16 (JD-5006) and 23 (JD-5037) showing little brain presence as indicated by tissue distribution and receptor occupancy studies, are described. Effects with one of these compounds on plasma triglyceride levels, liver weight and enzymes, glucose tolerance and insulin sensitivity support the approach that blockade of peripheral CB(1) receptors is sufficient to produce many of the beneficial metabolic effects of globally active CB(1) blockers. Thus, PR CB(1) inverse agonists may indeed represent a safer alternative to highly brain-penetrant agents for the treatment of metabolic disorders, including diabetes, liver diseases, dyslipidemias, and obesity.
Assuntos
Amidinas/farmacologia , Encefalopatias Metabólicas/tratamento farmacológico , Pirazóis/farmacologia , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/antagonistas & inibidores , Amidinas/síntese química , Amidinas/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/química , Proteínas Recombinantes/agonistas , Proteínas Recombinantes/antagonistas & inibidores , Relação Estrutura-Atividade , SulfonamidasRESUMO
Obesity-related leptin resistance manifests in loss of leptin's ability to reduce appetite and increase energy expenditure. Obesity is also associated with increased activity of the endocannabinoid system, and CB(1) receptor (CB(1)R) inverse agonists reduce body weight and the associated metabolic complications, although adverse neuropsychiatric effects halted their therapeutic development. Here we show that in mice with diet-induced obesity (DIO), the peripherally restricted CB(1)R inverse agonist JD5037 is equieffective with its brain-penetrant parent compound in reducing appetite, body weight, hepatic steatosis, and insulin resistance, even though it does not occupy central CB(1)R or induce related behaviors. Appetite and weight reduction by JD5037 are mediated by resensitizing DIO mice to endogenous leptin through reversing the hyperleptinemia by decreasing leptin expression and secretion by adipocytes and increasing leptin clearance via the kidney. Thus, inverse agonism at peripheral CB(1)R not only improves cardiometabolic risk in obesity but has antiobesity effects by reversing leptin resistance.