RESUMO
A series of 2,3,3a,4-tetrahydro-1H-pyrrolo[3,4-c]isoquinolin-5(9bH)-ones is described, several examples of which exhibit potent 5-HT(2C) agonism with excellent selectivity over the closely related 5-HT(2A) and 5-HT(2B) receptors. Compounds such as 38 and 44 were shown to be effective in reducing food intake in an acute rat feeding model.
Assuntos
Compostos Heterocíclicos com 3 Anéis/síntese química , Isoquinolinas/química , Pirróis/química , Pirróis/síntese química , Receptor 5-HT2C de Serotonina/química , Agonistas do Receptor 5-HT2 de Serotonina/síntese química , Animais , Meia-Vida , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Humanos , Isoquinolinas/síntese química , Isoquinolinas/farmacocinética , Masculino , Pirróis/farmacocinética , Ratos , Ratos Sprague-Dawley , Receptor 5-HT2A de Serotonina/química , Receptor 5-HT2A de Serotonina/metabolismo , Receptor 5-HT2B de Serotonina/química , Receptor 5-HT2B de Serotonina/metabolismo , Receptor 5-HT2C de Serotonina/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina/química , Agonistas do Receptor 5-HT2 de Serotonina/farmacocinética , Relação Estrutura-AtividadeRESUMO
The 5-HT2C receptor has been implicated as a critical regulator of appetite. Small molecule activation of the 5-HT2C receptor has been shown to affect food intake and regulate body weight gain in rodent models and more recently in human clinical trials. Therefore, 5-HT2C is a well validated target for anti-obesity therapy. The synthesis and structure-activity relationships of a series of novel tetrahydropyrazinoisoquinolinone 5-HT2C receptor agonists are presented. Several members of this series were identified as potent 5-HT2C receptor agonists with high functional selectivity against the 5-HT2A and 5-HT2B receptors and reduced food intake in an acute rat feeding model upon oral dosing.
Assuntos
Isoquinolinas/farmacologia , Pirazinas/farmacologia , Receptor 5-HT2C de Serotonina/metabolismo , Animais , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ingestão de Alimentos/efeitos dos fármacos , Humanos , Isoquinolinas/síntese química , Isoquinolinas/química , Modelos Moleculares , Estrutura Molecular , Pirazinas/síntese química , Pirazinas/química , Ratos , Relação Estrutura-AtividadeRESUMO
Obesity remains a significant public health issue leading to Type II diabetes and cardiovascular disease. CB1 antagonists have been shown to suppress appetite and reduce body weight in animal models as well as in humans. Evaluation of pre-clinical CB1 antagonists to establish relationships between in vitro affinity and in vivo efficacy parameters are enhanced by ex vivo receptor occupancy data. Synthesis and biological evaluation of a novel and highly selective radiolabeled CB1 antagonist is described. The radioligand was used to conduct ex vivo receptor occupancy studies.
Assuntos
Fármacos Antiobesidade/química , Fármacos Antiobesidade/farmacologia , Ensaio Radioligante/métodos , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB1 de Canabinoide/metabolismo , Animais , Encéfalo/diagnóstico por imagem , Humanos , Obesidade/tratamento farmacológico , Radiografia , RatosRESUMO
Agonists of the 5-HT(2C) receptor have been shown to suppress appetite and reduce body weight in animal models as well as in humans. However, agonism of the related 5-HT(2B) receptor has been associated with valvular heart disease. Synthesis and biological evaluation of a series of novel and highly selective dihydroquinazolinone-derived 5-HT(2C) agonists with no detectable agonism of the 5-HT(2B) receptor is described. Among these, compounds (+)-2a and (+)-3c were identified as potent and highly selective agonists which exhibited weight loss in a rat model upon oral dosing.
Assuntos
Fármacos Antiobesidade/química , Obesidade/tratamento farmacológico , Quinazolinonas/química , Agonistas do Receptor 5-HT2 de Serotonina , Agonistas do Receptor de Serotonina/química , Administração Oral , Animais , Fármacos Antiobesidade/administração & dosagem , Fármacos Antiobesidade/metabolismo , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/fisiologia , Humanos , Masculino , Obesidade/metabolismo , Ligação Proteica/fisiologia , Quinazolinonas/administração & dosagem , Ratos , Ratos Sprague-Dawley , Receptor 5-HT2C de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/administração & dosagem , Agonistas do Receptor de Serotonina/metabolismoRESUMO
Robust pharmaceutical treatment of obesity has been limited by the undesirable side-effect profile of currently marketed therapies. This paper describes the synthesis and optimization of a new class of pyrazinoisoindolone-containing, selective 5-HT2C agonists as antiobesity agents. Key to optimization of the pyrazinoisoindolone core was the identification of the appropriate substitution pattern and functional groups which led to the discovery of (R)-9-ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol-6(2H)-one (58), a 5-HT2C agonist with >300-fold functional selectivity over 5-HT2B and >70-fold functional selectivity over 5-HT2A. Oral dosing of 58 reduced food intake in an acute rat feeding model, which could be completely reversed by a selective 5-HT2C antagonist and caused a reduction in body weight gain in a 4-day rat model.
Assuntos
Fármacos Antiobesidade/síntese química , Indóis/síntese química , Pirazinas/síntese química , Agonistas do Receptor 5-HT2 de Serotonina , Administração Oral , Animais , Fármacos Antiobesidade/química , Fármacos Antiobesidade/farmacologia , Barreira Hematoencefálica/metabolismo , Linhagem Celular , Condicionamento Operante , Comportamento Alimentar/efeitos dos fármacos , Humanos , Indóis/química , Indóis/farmacologia , Isoindóis , Masculino , Camundongos , Necrose , Células Parietais Gástricas/efeitos dos fármacos , Células Parietais Gástricas/patologia , Pirazinas/química , Pirazinas/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Aumento de Peso/efeitos dos fármacosRESUMO
In order to explore the relationship between the anorectic effect of 3-carboxy-4-octyl-2-methylenebutyrolactone (C75) and its pharmacokinetic properties, studies of in vivo and in vitro pharmacological characterization of C75 were performed in Fischer rats. In a quantitative measurement of food intake, we determined that appetite suppression by C75 takes place within 4 h. The C(max) for C75 of 2.6+/-1.5 microM was reached within 1-4 h after intraperitoneal administration at 30 mg/kg, a drug level that causes complete blockade of food intake. However, this concentration is substantially lower than the effective concentration used to inhibit rat fatty acid synthase enzyme activity in vitro (IC50: approximately 200 microM) and hypothalamic enzyme activity was found not to be inhibited by intraperitoneal administration of C75 at 30 mg/kg. Instead, a dramatic induction of c-Fos expression was found in area postrema. Collectively, these data indicate that the anorectic effect of C75 is independent of its inhibition of fatty acid synthase in the hypothalamus.
Assuntos
4-Butirolactona/análogos & derivados , 4-Butirolactona/farmacologia , Ácido Graxo Sintases/antagonistas & inibidores , Hipotálamo/efeitos dos fármacos , 4-Butirolactona/sangue , 4-Butirolactona/farmacocinética , Animais , Depressores do Apetite/farmacocinética , Depressores do Apetite/farmacologia , Comportamento Animal/efeitos dos fármacos , Northern Blotting , Ciclobutanos/farmacologia , Relação Dose-Resposta a Droga , Ácido Graxo Sintases/genética , Ácido Graxo Sintases/metabolismo , Fenfluramina/farmacologia , Privação de Alimentos , Hipotálamo/enzimologia , Immunoblotting , Injeções Intraperitoneais , Injeções Intraventriculares , Cinética , Masculino , Fentermina/farmacologia , RNA/genética , RNA/metabolismo , Distribuição Aleatória , Ratos , Ratos Endogâmicos F344 , Fatores de TempoRESUMO
Several strategies have been employed to reduce the long in vivo half-life of our lead CB1 antagonist, triazolopyridazinone 3, to differentiate the pharmacokinetic profile versus the lead clinical compounds. An in vitro and in vivo clearance data set revealed a lack of correlation; however, when compounds with <5% free fraction were excluded, a more predictable correlation was observed. Compounds with log P between 3 and 4 were likely to have significant free fraction, so we designed compounds in this range to give more predictable clearance values. This strategy produced compounds with desirable in vivo half-lives, ultimately leading to the discovery of compound 46. The progression of compound 46 was halted due to the contemporaneous marketing and clinical withdrawal of other centrally acting CB1 antagonists; however, the design strategy successfully delivered a potent CB1 antagonist with the desired pharmacokinetic properties and a clean off-target profile.