RESUMO
The design, synthesis and structure-activity relationships of a novel class of N-phenylpyridone MCH1R antagonists are described. The core part of the N-phenylpyridone structure was newly designed and the side chain moieties that were attached to the core part were extensively explored. As a result of optimization of the N-phenylpyridone leads, we successfully developed the orally available, and brain-penetrable MCH1R selective antagonist 7c, exhibiting excellent anti-obese effect in diet-induced obese (DIO) mice.
Assuntos
Piridonas/química , Receptores de Somatostatina/antagonistas & inibidores , Animais , Avaliação Pré-Clínica de Medicamentos , Humanos , Camundongos , Camundongos Obesos , Piridonas/síntese química , Piridonas/farmacocinética , Ratos , Receptores de Somatostatina/metabolismo , Relação Estrutura-AtividadeRESUMO
G-protein-coupled receptors (GPCRs) constitute the largest family of transmembrane receptors and regulate a variety of physiological and disease processes. Although the roles of many non-odorant GPCRs have been identified in vivo, several GPCRs remain orphans (oGPCRs). The gastrointestinal (GI) tract is the largest endocrine organ and is a promising target for drug discovery. Given their close link to physiological function, the anatomical and histological expression profiles of benchmark GI-related GPCRs, such as the cholecystokinin-1 receptor and GPR120, and 106 oGPCRs were investigated in the mucosal and muscle-myenteric nerve layers in the GI tract of C57BL/6J mice by quantitative real-time polymerase chain reaction. The mRNA expression patterns of these benchmark molecules were consistent with previous in situ hybridization and immunohistochemical studies, validating the experimental protocols in this study. Of 96 oGPCRs with significant mRNA expression in the GI tract, several oGPCRs showed unique expression patterns. GPR85, GPR37, GPR37L1, brain-specific angiogenesis inhibitor (BAI) 1, BAI2, BAI3, and GPRC5B mRNAs were preferentially expressed in the muscle-myenteric nerve layer, similar to GPCRs that are expressed in both the central and enteric nerve systems and that play multiple regulatory roles throughout the gut-brain axis. In contrast, GPR112, trace amine-associated receptor (TAAR) 1, TAAR2, and GPRC5A mRNAs were preferentially expressed in the mucosal layer, suggesting their potential roles in the regulation of secretion, immunity, and epithelial homeostasis. These anatomical and histological mRNA expression profiles of oGPCRs provide useful clues about the physiological roles of oGPCRs in the GI tract.
Assuntos
Trato Gastrointestinal/metabolismo , Mucosa/metabolismo , Receptores Acoplados a Proteínas G/biossíntese , Animais , Quimiocinas CC , Trato Gastrointestinal/anatomia & histologia , Expressão Gênica , Camundongos , Camundongos Endogâmicos C57BL , Especificidade de Órgãos , RNA Mensageiro , Receptores da Colecistocinina/genética , Receptores da Colecistocinina/metabolismo , Receptores Acoplados a Proteínas G/genética , Transcrição GênicaRESUMO
Novel phenethylpyridone derivatives were identified as potent human melanin-concentrating hormone 1 receptor (MCH-1R) antagonists. A search for surrogates for the 4-(2-aminoethoxy)phenyl moiety of 1 resulted in discovery of 2-[4-(aminomethyl)phenyl]ethyl substructure as in 6a. Successive optimization of the right-hand moiety led to the identification of a number of potent derivatives.
Assuntos
Fármacos Antiobesidade/síntese química , Piridonas/síntese química , Receptores de Somatostatina/antagonistas & inibidores , Animais , Fármacos Antiobesidade/química , Fármacos Antiobesidade/farmacologia , Células CHO , Cricetinae , Cricetulus , Descoberta de Drogas , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Piridonas/química , Piridonas/farmacologia , Receptores de Somatostatina/metabolismo , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/metabolismo , Relação Estrutura-AtividadeRESUMO
Novel imidazoline derivatives were discovered to be potent neuropeptide Y Y5 receptor antagonists. High-throughput screening of Merck sample collections against the human Y5 receptor resulted in the identification of 2,4,4-triphenylimidazoline (1), which had an IC(50) of 54nM. Subsequent optimization led to the identification of several potent derivatives.
Assuntos
Química Farmacêutica/métodos , Imidazóis/química , Receptores de Neuropeptídeo Y/química , Animais , Encéfalo/metabolismo , Ácidos Carboxílicos/química , Líquido Cefalorraquidiano/metabolismo , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Camundongos , Modelos Químicos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
We have developed and characterized [(35)S]4a as a potent and selective radioligand for melanin-concentrating hormone 1-receptor (MCH1R). Compound [(35)S]4a showed appreciable specific signals in brain slices prepared from wild-type mice but not from MCH1R deficient mice, confirming the specificity and utility of [(35)S]4a as a selective MCH1R radioligand for ex vivo receptor occupancy assays.
Assuntos
Benzofuranos/química , Receptores de Somatostatina/metabolismo , Compostos de Espiro/química , Sulfonamidas/química , Sequência de Aminoácidos , Animais , Benzofuranos/síntese química , Benzofuranos/farmacologia , Encéfalo/metabolismo , Células CHO , Cricetinae , Cricetulus , Humanos , Cinética , Camundongos , Camundongos Knockout , Receptores de Somatostatina/antagonistas & inibidores , Receptores de Somatostatina/deficiência , Compostos de Espiro/síntese química , Compostos de Espiro/farmacologia , Sulfonamidas/síntese química , Sulfonamidas/farmacologiaRESUMO
A series of 2-aminobenzimidazole-based MCH1R antagonists was identified by core replacement of the aminoquinoline lead 1. Subsequent modification of the 2- and 5-positions led to improvement in potency and intrinsic clearance. Compound 25 exhibited good plasma and brain exposure, and attenuated MCH induced food intake at 30mg/kg PO in rats.
Assuntos
Fármacos Antiobesidade/química , Benzimidazóis/química , Receptores de Somatostatina/antagonistas & inibidores , Animais , Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/farmacocinética , Benzimidazóis/síntese química , Benzimidazóis/farmacocinética , Ingestão de Alimentos/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores de Somatostatina/metabolismo , Relação Estrutura-AtividadeRESUMO
A series of imidazo[1,2-a]pyridine derivatives was identified and evaluated for MCH1R binding and antagonistic activity. Introduction of a methyl substituent at the 3-position of imidazo[1,2-a]pyridine provided compounds with a significant improvement in MCH1R affinity. Representative compounds in this series exhibited good potency and brain exposure in rats.
Assuntos
Fármacos Antiobesidade/química , Piridinas/química , Receptores de Somatostatina/antagonistas & inibidores , Animais , Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/farmacologia , Células CHO , Cricetinae , Cricetulus , Descoberta de Drogas , Humanos , Piridinas/síntese química , Piridinas/farmacologia , Ratos , Receptores de Somatostatina/metabolismo , Relação Estrutura-AtividadeRESUMO
A series of trans-3-oxospiro[(aza)isobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide derivatives were synthesized and profiled for NPY Y5 binding affinity, brain and CSF penetrability in rats, and susceptibility to human and mouse P-glycoprotein transporters in order to develop a PET ligand. Compound 12b exhibited an acceptable profile for a PET ligand, and [(11)C]12b was successfully utilized in clinical settings as a Y5 PET ligand.
Assuntos
Encéfalo/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Ensaio Radioligante/métodos , Receptores de Neuropeptídeo Y/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Encéfalo/metabolismo , Linhagem Celular , Líquido Cefalorraquidiano/diagnóstico por imagem , Humanos , Ligantes , Camundongos , Plasma/diagnóstico por imagem , Ligação Proteica , Ratos , Relação Estrutura-AtividadeRESUMO
A series of spiroindoline-3,4'-piperidine derivatives were synthesized and evaluated for their binding affinities and antagonistic activities at Y5 receptors. Potent Y5 antagonists were tested for their oral bioavailabilities and brain penetration in rats. Some of the antagonists showed good oral bioavailability and/or good brain penetration. In particular, compound 6e was orally bioavailable and brain penetrant, and oral administration of 6e inhibited bPP-induced food intake in rats with a minimum effective dose of 10mg/kg.
Assuntos
Química Farmacêutica/métodos , Indóis/administração & dosagem , Indóis/farmacologia , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Receptores de Neuropeptídeo Y/química , Administração Oral , Aminas/química , Animais , Disponibilidade Biológica , Encéfalo/efeitos dos fármacos , Desenho de Fármacos , Concentração Inibidora 50 , Isocianatos/química , Modelos Químicos , Biblioteca de Peptídeos , Ratos , Ureia/químicaRESUMO
Optimization of high-throughput screening hit 1a led to the identification of a novel spiro-piperidine class of melanin-concentrating hormone 1 receptor (MCH-1R) antagonists. Compound 3c was identified as a highly potent and selective MCH-1R antagonist, which has an IC(50) value of 0.09 nM at hMCH-1R. The synthesis and structure-activity relationships of the novel spiro-piperidine MCH-1R antagonists are described.
Assuntos
Piperidinas/química , Receptores de Somatostatina/antagonistas & inibidores , Compostos de Espiro/química , Linhagem Celular , Descoberta de Drogas , Humanos , Piperidinas/síntese química , Piperidinas/farmacologia , Receptores de Somatostatina/metabolismo , Compostos de Espiro/síntese química , Compostos de Espiro/farmacologia , Relação Estrutura-AtividadeRESUMO
Continuing medicinal chemistry studies to identify spiropiperidine-derived NPY Y5 receptor antagonists are described. Aryl urea derivatives of a variety of spiropiperidines were tested for their NPY Y5 receptor binding affinities. Of the spiropiperidines so far examined, spiro[3-oxoisobenzofurane-1(3H),4'-piperidine] was a useful scaffold for producing orally active NPY Y5 receptor antagonists. Oral administration of 5c significantly inhibited the Y5 agonist-induced food intake in rats with a minimum effective dose of 3mg/kg. In addition, this compound was efficacious in decreasing body weight in diet-induced obese mice.
Assuntos
Fármacos Antiobesidade/química , Piperidinas/química , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Compostos de Espiro/química , Ureia/análogos & derivados , Administração Oral , Animais , Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/farmacologia , Ingestão de Alimentos , Humanos , Camundongos , Piperidinas/síntese química , Piperidinas/farmacologia , Ratos , Receptores de Neuropeptídeo Y/metabolismo , Compostos de Espiro/síntese química , Compostos de Espiro/farmacologia , Ureia/síntese química , Ureia/farmacologia , Redução de PesoRESUMO
Spiroindoline urea derivatives, designed to act as NPY Y5 receptor antagonists, were synthesized and their structure-activity relationships were investigated. Of these derivatives, compound 3a showed good Y5 binding affinity with favorable pharmacokinetic properties. Compound 3a significantly inhibited bPP Y5 agonist-induced food intake in rats, and suppressed body weight gain in DIO mice.
Assuntos
Fármacos Antiobesidade/química , Fármacos Antiobesidade/farmacologia , Indóis/química , Indóis/farmacologia , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Receptores de Neuropeptídeo Y/metabolismo , Animais , Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/farmacocinética , Disponibilidade Biológica , Peso Corporal/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Indóis/síntese química , Indóis/farmacocinética , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Receptores de Neuropeptídeo Y/agonistas , Compostos de Espiro/síntese química , Compostos de Espiro/química , Compostos de Espiro/farmacocinética , Compostos de Espiro/farmacologia , Relação Estrutura-AtividadeRESUMO
A series of 2-pyridone-containing imidazoline derivatives was synthesized and evaluated as neuropeptide Y Y5 receptor antagonists. Optimization of the 2-pyridone structure on the 2-position of the imidazoline ring led to identification of 1-(difluoromethyl)-5-[(4S,5S)-4-(4-fluorophenyl)-4-(6-fluoropyridin-3-yl)-5-methyl-4,5-dihydro-1H-imidazol-2-yl]pyridin-2(1H)-one (7m). Compound 7m displayed statistically significant inhibition of food intake in an agonist-induced food intake model in SD rats and no adverse cardiovascular effects in anesthetized dogs. In addition, markedly higher brain penetrability and a lower plasma Occ90 value were observed in P-gp-deficient mdr1a (-/-) mice compared to mdr1a (+/+) mice after oral administration of 7m.
Assuntos
Fármacos Antiobesidade/química , Imidazolinas/química , Piridonas/química , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/deficiência , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/farmacocinética , Cães , Descoberta de Drogas , Humanos , Imidazolinas/síntese química , Imidazolinas/farmacocinética , Camundongos , Piridonas/síntese química , Piridonas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Neuropeptídeo Y/metabolismo , Relação Estrutura-AtividadeRESUMO
A series of trans-3-oxospiro[(aza)isobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide derivatives were synthesized to identify potent NPY Y5 receptor antagonists. Of the compounds, 21j showed high Y5 binding affinity, metabolic stability and brain and cerebrospinal fluid (CSF) penetration, and low susceptibility to P-glycoprotein transporters. Oral administration of 21j significantly inhibited the Y5 agonist-induced food intake in rats with a minimum effective dose of 1mg/kg. This compound was selected for proof-of-concept studies in human clinical trials.
Assuntos
Amidas/síntese química , Benzofuranos/síntese química , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Compostos de Espiro/síntese química , Transportadores de Cassetes de Ligação de ATP/metabolismo , Administração Oral , Amidas/farmacologia , Animais , Benzofuranos/farmacologia , Encéfalo/metabolismo , Líquido Cefalorraquidiano/metabolismo , Estabilidade de Medicamentos , Ingestão de Alimentos/efeitos dos fármacos , Ratos , Compostos de Espiro/farmacologiaRESUMO
Syntheses and structure-activity relationships of a novel class of 2-[3-oxospiro[isobenzofuran-1(3H),1'-cyclohexan]-4'-yl]benzimidazole NPY Y5 receptor antagonists are described. Optimization of the lead compound 2a by incorporating substituents into the 5-position or into both the 5- and 6-positions of the benzimidazole core part led to the identification of 5-(5-methyl-1,2,4-oxadiazol-2-yl)benzimidazole (2r: IC(50)=3.3 nM) and 5-(2-methyltetrazol-5-yl)benzimidazole (2u: IC(50)=5.9 nM), both of which are potent, selective, and orally bioavailable Y5 receptor antagonists.
Assuntos
Benzimidazóis/síntese química , Benzimidazóis/farmacologia , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Administração Oral , Benzimidazóis/química , Encéfalo/efeitos dos fármacos , Técnicas de Química Combinatória , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Design, syntheses, and structure-activity relationships of a novel class of 2-{3-oxospiro[isobenzofuran-1(3H),4'-piperidin]-1'-yl}benzimidazole NPY Y5 receptor antagonists are described. The benzimidazole structures were newly designed based on the urea linkage of our prototype Y5 receptor antagonists (2 and 3). By optimizing substituents on the benzimidazole core part of the lead compound 5a, we were able to develop a potent, orally available, and brain-penetrable Y5 selective antagonist (5k).
Assuntos
Benzimidazóis/síntese química , Benzimidazóis/farmacologia , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Administração Oral , Animais , Benzimidazóis/química , Encéfalo/efeitos dos fármacos , Técnicas de Química Combinatória , Desenho de Fármacos , Estrutura Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
Several lines of epidemiological evidence have suggested that non-alcoholic steatohepatitis (NASH) is closely associated with obesity in humans. However, the precise mechanisms of the progression of NASH and its key metabolic abnormalities remain to be elucidated. We found that long-term high-fat diet (HFD) exposure induces NASH, with excess body weight, hyperinsulinemia and hypercholesteremia in mice. Longitudinal analysis of the model showed that steatohepatitis was induced after onset of metabolic abnormalities. In addition, we found that expression of MCP-1 mRNA was induced in the liver before induction of TNFalpha and type I collagen alpha1 mRNAs, and prior to onset of steatohepatitis. We confirmed that hepatic MCP-1 contents were increased in mice fed HFD for 50 weeks, although the precise role of MCP-1 in the development of NASH remains to be addressed. The mouse model was also characterized by moderate reductions in catalase activity and glutathione content, as well as by overexpression of fatty acid synthase, acetyl-CoA carboxylase 1 and FAT/CD36 mRNAs in the liver. The murine NASH model apparently mimics clinical aspects of the condition and provides insight into NASH.
RESUMO
QRFP, an RFamide peptide, was recently identified as an endogenous ligand of an orphan G protein-coupled receptor, GPR103. Recent investigation revealed that acute intracerebroventricular (ICV) administration of QRFP26/P518/26RFa, a constitutive part of QRFP43 (43-amino acid-residue form of QRFP), increases appetite in mice, but its role in long-term energy homeostasis remains unknown. In the present study, we examined the effects of chronic administration of QRFP43 on feeding behavior, body weight regulation, and energy expenditure in mice. Intracerebroventricular infusion of QRFP43 for 13 d resulted in a significant increase in body weight and fat mass with hyperphagia. Weight gain and hyperphagia were more evident when mice were fed a moderately high-fat diet. Pair feeding of QRFP43-infused mice did not increase body weight but significantly increased fat mass and plasma concentrations of insulin, leptin, and cholesterol when compared with controls. Moreover, significant decreases in rectal temperature and expression of brown adipose tissue uncoupling protein-1 mRNA were observed in QRFP43-infused ad libitum- and pair-fed mice. The present results suggest that QRFP plays an important role in energy homeostasis by regulating appetite and energy expenditure.
Assuntos
Hiperfagia/induzido quimicamente , Neuropeptídeos/farmacologia , Obesidade/induzido quimicamente , Termogênese/efeitos dos fármacos , Animais , Injeções Intraventriculares , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacosRESUMO
Nonalcoholic steatohepatitis (NASH) is a chronic liver disease closely associated with obesity, type 2 diabetes and hyperlipidemia. For further understanding of NASH, development and characterization of appropriate animal models with metabolic abnormalities is important. Based on the "two hit theory", we tried to develop a new murine model of NASH with metabolic abnormalities. For the first hit to achieve metabolic abnormalities, a high-fat diet (HFD: 60 cal% fat) was fed to C57BL/6 mice for 10 weeks. For the second hit, 30mg/kg tetracycline was injected intraperitoneally once daily for 10 days. The HFD-fed mice treated with tetracycline showed robust increases in triglyceride content and expression levels of proinflammatory cytokine mRNAs in the liver. In addition, plasma ALT levels were significantly elevated by this combinational treatment. Furthermore, histological examination demonstrated that combinational treatment induced multifocal inflammatory cellular infiltration in the livers of all mice, and thus caused mild steatohepatitis. The HFD-tetracycline model could be useful for further understanding NASH.
RESUMO
Melanin-concentrating hormone (MCH) is a cyclic orexigenic peptide expressed in the lateral hypothalamus, which plays an important role in regulating energy balance. To elucidate the physiological role of MCH in obesity development, the present study examined the effect of a selective MCH1 receptor (MCH1R) antagonist in the diet-induced obesity mouse model. The MCH1R antagonist has high affinity and selectivity for MCH-1R and potently inhibits intracerebroventricularly injected MCH-induced food intake in Sprague Dawley rats. Chronic intracerebroventricular infusion of the MCH1R antagonist (7.5 microg/d) completely suppressed body weight gain in diet-induced obese mice during the treatment periods and significantly decreased cumulative food intake, by 14%. Carcass analysis showed that the MCH1R antagonist resulted in a selective decrease of body fat in the diet-induced obese mice. In addition, the MCH1R antagonist ameliorated the obesity-related hypercholesterolemia, hyperinsulinemia, hyperglycemia, and hyperleptinemia. These results indicate that MCH has a major role in the development of diet-induced obesity in mice and that a MCH1R antagonist might be a useful candidate as an antiobesity agent.