RESUMO
11ß-Hydroxysteroid dehydrogenase type 1 (11ß-HSD1) is considered a potential therapeutic target in the treatment of type 2 diabetes mellitus. In this study, we investigated the pharmacological properties of HIS-388 (N-[(1R,2s,3S,5s,7s)-5-hydroxyadamantan-2-yl]-3-(pyridin-2-yl) isoxazole-4-carboxamide), a newly synthesized 11ß-HSD1 inhibitor, using several mouse models. In cortisone pellet-implanted mice in which hypercortisolism and hyperinsulinemia occur, single administration of HIS-388 exhibited potent and prolonged suppression of plasma cortisol and lowered plasma insulin levels. These effects were more potent than those achieved using the same dose of other 11ß-HSD1 inhibitors (carbenoxolone and compound 544 [3-[(1s,3s)-adamantan-1-yl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepine]), indicating that HIS-388 potently and continuously suppresses 11ß-HSD1 enzyme activity in vivo. In diet-induced obese mice, HIS-388 significantly decreased fasting blood glucose, plasma insulin concentration, and homeostasis model assessment-insulin resistance score, and ameliorated insulin sensitivity. In addition, HIS-388 significantly reduced body weight and suppressed the elevation of blood glucose during the pyruvate tolerance test. In nongenetic type 2 diabetic mice with disease induced by a high-fat diet and low-dose streptozotocin, HIS-388 also significantly decreased postprandial blood glucose and plasma insulin levels and improved glucose intolerance. The effects of HIS-388 on glucose metabolism were indistinguishable from those of an insulin sensitizer, pioglitazone. Our results suggest that HIS-388 is a potent agent against type 2 diabetes. Moreover, amelioration of diabetic symptoms by HIS-388 was at least in part attributable to an antiobesity effect or improvement of hepatic insulin resistance. Therefore, potent and long-lasting inhibition of 11ß-HSD1 enzyme activity may be an effective approach for the treatment of type 2 diabetes and obesity-associated disease.
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Adamantano/análogos & derivados , Diabetes Mellitus Experimental/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Intolerância à Glucose , Hipoglicemiantes/uso terapêutico , Resistência à Insulina , Isoxazóis/farmacologia , Obesidade/tratamento farmacológico , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Adamantano/farmacologia , Adamantano/uso terapêutico , Administração Oral , Animais , Azepinas/uso terapêutico , Carbenoxolona/uso terapêutico , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacologia , Feminino , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacologia , Isoxazóis/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Pioglitazona , Tiazolidinedionas/uso terapêutico , Triazóis/uso terapêuticoRESUMO
A series of novel 5-trans-hydroxyadamantan-2-yl-5,6,7,8-tetrahydropyrazolo[4,3-c]azepin-4(1H)-ones that inhibit 11beta-hydroxysteroid dehydrogenase type 1 are described. We discovered these 7-membered cyclic amide derivatives by introducing a distinctive linker through pharmacophore analysis of known ligands included in X-ray co-crystal structures. Further optimization using docking studies led to highly potent inhibitors 15b and 27, which furthermore showed the potent efficacy in in vivo studies.
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Amidas/química , Inibidores Enzimáticos/química , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Amidas/síntese química , Amidas/metabolismo , Animais , Sítios de Ligação , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Humanos , Interações Hidrofóbicas e Hidrofílicas , Camundongos , Simulação de Acoplamento Molecular , Ligação Proteica , Estrutura Terciária de Proteína , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A series of novel 3-amino-N-(4-aryl-1,1-dioxothian-4-yl)butanamides were investigated as dipeptidyl peptidase IV (DPP-4) inhibitors. Introduction of a 4-phenylthiazol-2-yl group showed highly potent DPP-4 inhibitory activity. Among various derivatives, (3R)-3-amino-N-(4-(4-phenylthiazol-2-yl)-tetrahydro-2H-thiopyran-4-yl)-4-(2,4,5-trifluorophenyl)butanamide 1,1-dioxide (30) reduced blood glucose excursion in an oral glucose tolerance test by oral administration.
Assuntos
Amidas/química , Dipeptidil Peptidase 4/química , Inibidores da Dipeptidil Peptidase IV/química , Piranos/química , Tiazóis/química , Administração Oral , Amidas/síntese química , Amidas/metabolismo , Animais , Glicemia/metabolismo , Células CACO-2 , Dipeptidil Peptidase 4/sangue , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/síntese química , Inibidores da Dipeptidil Peptidase IV/metabolismo , Teste de Tolerância a Glucose , Humanos , Camundongos , Camundongos Endogâmicos ICR , Ligação Proteica , Piranos/síntese química , Piranos/metabolismo , Tiazóis/síntese química , Tiazóis/metabolismoRESUMO
Optimization starting with our lead compound 1 (IC(50)=4.9 nM) led to the identification of pyrrolidinyl phenylurea derivatives. Further modification toward improvement of the bioavailability provided (R)-1-(1-((6-fluoronaphthalen-2-yl)methyl)pyrrolidin-3-yl)-3-(2-(2-hydroxyethoxy)phenyl)urea 32 (IC(50)=1.7 nM), a potent and orally active CCR3 antagonist.
Assuntos
Compostos de Fenilureia/química , Pirrolidinas/química , Receptores CCR3/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Meia-Vida , Macaca fascicularis , Compostos de Fenilureia/síntese química , Compostos de Fenilureia/farmacocinética , Pirrolidinas/síntese química , Pirrolidinas/farmacocinética , Receptores CCR3/metabolismoRESUMO
The synthesis and structure-activity relationships of ureas as CCR3 antagonists are described. Optimization starting with lead compound 2 (IC(50)=190 nM) derived from initial screening hit compound 1 (IC(50)=600 nM) led to the identification of (S)-N-((1R,3S,5S)-8-((6-fluoronaphthalen-2-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-N-(2-nitrophenyl)pyrrolidine-1,2-dicarboxamide 27 (IC(50)=4.9 nM) as a potent CCR3 antagonist.
Assuntos
Receptores CCR3/antagonistas & inibidores , Ureia/análogos & derivados , Avaliação Pré-Clínica de Medicamentos , Humanos , Naftalenos/síntese química , Naftalenos/química , Naftalenos/metabolismo , Prolina/química , Ligação Proteica , Pirrolidinas/síntese química , Pirrolidinas/química , Pirrolidinas/metabolismo , Receptores CCR3/metabolismo , Relação Estrutura-Atividade , Ureia/síntese química , Ureia/metabolismoRESUMO
We report the discovery and structure-activity relationship of 2,6-disubstituted pyrazines, which are potent and selective CK2 inhibitors. Lead compound 1 was identified, and derivatives were prepared to develop potent inhibitory activity. As a result, we obtained compound 7, which was the smallest unit that retained potency. Then, introducing an aminoalkyl group at the 6-position of the indazole ring resulted in improved efficacy in both enzymatic and cell-based CK2 inhibition assays. Moreover, compound 13 showed selectivity against other kinases and in vivo efficacy in a rat nephritis model. These results show that 2,6-disubstituted pyrazines have potential as therapeutic agents for nephritis.
Assuntos
Caseína Quinase II/antagonistas & inibidores , Indazóis/química , Inibidores de Proteínas Quinases/química , Pirazinas/química , Animais , Sítios de Ligação , Caseína Quinase II/metabolismo , Simulação por Computador , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Indazóis/síntese química , Indazóis/uso terapêutico , Injeções Intraperitoneais , Nefrite/tratamento farmacológico , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/uso terapêutico , Estrutura Terciária de Proteína , Pirazinas/síntese química , Pirazinas/uso terapêutico , Ratos , Relação Estrutura-AtividadeRESUMO
Our laboratory has identified several acrylamide derivatives with potent CCR3 inhibitory activity. In the present study, we evaluated the in vitro metabolic stability (CL(int); mL/min/kg) of these compounds in human liver microsomes (HLMs), and assessed the relationship between their structures and CL(int) values. Among the compounds identified, N-{(3R)-1-[(6-fluoro-2-naphthyl)methyl]pyrrolidin-3-yl}-2-[1-(2-hydroxybenzoyl)piperidin-4-ylidene]acetamide (30j) was found to be a potent inhibitor (IC(50)=8.4nM) with a high metabolic stability against HLMs.
Assuntos
Acetamidas/síntese química , Acrilamidas/química , Antialérgicos/síntese química , Naftalenos/síntese química , Receptores CCR3/antagonistas & inibidores , Acetamidas/química , Acetamidas/farmacologia , Acrilamidas/síntese química , Acrilamidas/farmacocinética , Animais , Antialérgicos/química , Antialérgicos/farmacocinética , Haplorrinos , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Naftalenos/química , Naftalenos/farmacologia , Piperidinas/síntese química , Piperidinas/química , Piperidinas/farmacologia , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Receptores CCR3/metabolismo , TermodinâmicaRESUMO
Novel series of 3-amino-N-(4-aryl-1,1-dioxothian-4-yl)butanamides and 3-amino-N-(4-aryltetrahydropyran-4-yl)butanamides were synthesized and evaluated as dipeptidyl peptidase IV (DPP-IV) inhibitors. Derivatives incorporating the 6-substituted benzothiazole group showed highly potent DPP-IV inhibitory activity. Oral administration of (3R)-3-amino-4-(2,4,5-trifluorophenyl)-N-{4-[6-(2-methoxyethoxy)benzothiazol-2-yl]tetrahydropyran-4-yl}butanamide (12u) reduced blood glucose excursion in an oral glucose tolerance test.
Assuntos
Benzotiazóis/síntese química , Dipeptidil Peptidase 4/química , Inibidores da Dipeptidil Peptidase IV , Inibidores da Dipeptidil Peptidase IV/síntese química , Inibidores Enzimáticos/síntese química , Piranos/química , Administração Oral , Benzotiazóis/farmacologia , Glicemia/metabolismo , Química Farmacêutica/métodos , Inibidores da Dipeptidil Peptidase IV/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Esvaziamento Gástrico , Peptídeo 1 Semelhante ao Glucagon/química , Teste de Tolerância a Glucose , Humanos , Concentração Inibidora 50 , Células Secretoras de Insulina/metabolismo , Modelos QuímicosRESUMO
In our previous study on discovering novel types of CCR3 antagonists, we found a fluoronaphthalene derivative (1) that exhibited potent CCR3 inhibitory activity with an IC(50) value of 20 nM. However, compound 1 also inhibited human cytochrome P450 2D6 (CYP2D6) with an IC(50) value of 400 nM. In order to reduce its CYP2D6 inhibitory activity, we performed further systematic structural modifications on 1. In particular, we focused on reducing the number of lipophilic moieties in the biphenyl part of 1, using ClogD(7.4) values as the reference index of lipophilicity. This research led to the identification of N-{(3-exo)-8-[(6-fluoro-2-naphthyl)methyl]-8-azabicyclo[3.2.1]oct-3-yl}-3-(piperidin-1-ylcarbonyl)isonicotinamide 1-oxide (30) which showed comparable CCR3 inhibitory activity (IC(50)=23 nM) with much reduced CYP2D6 inhibitory activity (IC(50)=29,000 nM) compared with 1.
Assuntos
Inibidores do Citocromo P-450 CYP2D6 , Desenho de Fármacos , Hidrocarbonetos Fluorados/farmacologia , Naftalenos/farmacologia , Receptores CCR3/antagonistas & inibidores , Cálcio/química , Cálcio/metabolismo , Citoplasma/química , Citoplasma/metabolismo , Humanos , Hidrocarbonetos Fluorados/síntese química , Concentração Inibidora 50 , Naftalenos/síntese química , Receptores CCR3/metabolismo , Relação Estrutura-AtividadeRESUMO
A novel class of potent CCR3 receptor antagonists were designed and synthesized starting from N-{1-[(6-fluoro-2-naphthyl)methyl]piperidin-4-yl}benzamide (1),which was found by subjecting our chemical library to high throughput screening (HTS). The CCR3 inhibitory activity of the synthesized compounds against eotaxin-induced Ca(2+) influx was evaluated using CCR3-expressing preB cells. Systematic chemical modifications of 1 revealed that the 6-fluoro-2-naphthylmethyl moiety was essential for CCR3 inhibitory activity in this new series of CCR3 antagonists. Further structural modifications of the benzamide and piperidine moieties of 1 led to the identification of exo-N-{8-[(6-fluoro-2-naphthyl)methyl]-8-azabicyclo[3.2.1]oct-3- yl}biphenyl-2-carboxamide [corrected] (31) as a potent CCR3 antagonist with an IC(50) value of 0.020 microM.