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1.
Chem Pharm Bull (Tokyo) ; 67(8): 824-838, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31366832

RESUMO

We synthesized and evaluated novel 5-[2-(thiophen-2-yl)propan-2-yl]-4H-1,2,4-triazole derivatives as 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) inhibitors. Optimization of the thiophene ring and the substituents on the 1,2,4-triazole ring produced 3,4-dicyclopropyl-5-{2-[3-fluoro-5-(trifluoromethyl)thiophen-2-yl]propan-2-yl}-4H-1,2,4-triazole monohydrochloride (9a), which showed potent and selective inhibitory activity against human 11ß-HSD1. Compound 9a was also metabolically stable against human and mouse liver microsomes. Oral administration of 9a to diabetic ob/ob mice lowered corticosterone levels in adipose tissue, and thereby reduced plasma glucose and insulin levels in a dose-dependent manner.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Diabetes Mellitus Tipo 2/tratamento farmacológico , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Hipoglicemiantes/farmacologia , Triazóis/farmacologia , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Administração Oral , Animais , Diabetes Mellitus Tipo 2/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Células HEK293 , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/química , Masculino , Camundongos , Camundongos Obesos , Estrutura Molecular , Relação Estrutura-Atividade , Triazóis/administração & dosagem , Triazóis/química
2.
Biomed Res Int ; 2019: 5747436, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31214617

RESUMO

The metabolic syndrome is defined by impaired carbohydrate metabolism and lipid disorders and often accompanied by hypertension, all of which will lead to obesity and insulin resistance. Glucocorticoids play a regulatory role in the metabolism of proteins, lipids, and carbohydrates. There is growing evidence for a role of glucocorticoids in the development of the metabolic syndrome. The most important factor that regulates the access of endogenous glucocorticoids to receptors after release of glucocorticoids and their diffusion into the cytoplasm of target cells is the steroid metabolism involving a microsomal enzyme, 11ß-hydroxysteroid dehydrogenase (11ß-HSD). The changes in intracellular glucocorticoid metabolism in the pathogenesis of obesity indicate the participation of modulation by 11ß-HSD1, which may represent a new therapeutic target for the treatment of diseases such as type 2 diabetes, visceral obesity, or atherosclerosis. The aim of our study was to determine the fast and effective method to assess inhibition activity of compounds in relation with 11ß-hydroxysteroid dehydrogenase. The material for this study was human liver and kidney microsomes. In this study we used ELISA technique using 96-well microplates coated with antibodies which were specific for analyzed enzymes. The method can quickly and efficiently measure the inhibition of both 11ß-HSD1 and 11ß-HSD2. This method can be used to search for and determine inhibitors of this enzyme. Cortisone and cortisol were used as the substrates for corresponding enzyme assays. Furthermore, 3-N-allyl-2-thiouracil derivatives were used by us for comparison purposes in developing the method, although, due to their structure, those derivatives have not previously been considered as potential inhibitors of 11ß-HSD1. 3-N-Allyl-2-thiouracil derivatives are a group worth considering, because by modifying their structure (e.g., by introducing other substituents into the pyrimidine ring) it will be possible to obtain an increase in the activity of compounds in this regard. In conclusion, this study shows an efficient and fast method of determining inhibition activity of compounds in relation with 11ß-hydroxysteroid dehydrogenase.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/metabolismo , Inibidores Enzimáticos , Microssomos/enzimologia , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/antagonistas & inibidores , Aterosclerose/tratamento farmacológico , Aterosclerose/enzimologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/enzimologia , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Obesidade Abdominal/tratamento farmacológico , Obesidade Abdominal/enzimologia
3.
Chem Biodivers ; 16(6): e1900065, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31012543

RESUMO

11ß-Hydroxysteroid dehydrogenase type 1 (11ß-HSD1) is an enzyme that affects the body's cortisol levels. The inhibition of its activity can be used in the treatment of Cushing's syndrome, metabolic syndrome and type 2 diabetes. In this study, we synthesized new derivatives of 2-(methylamino)thiazol-4(5H)-one and tested their activity towards inhibition of 11ß-HSD1 and its isoform - 11ß-HSD2. The results were compared with the previously tested allyl derivatives. We found out that methyl derivatives are weaker inhibitors of 11ß-HSD1 in comparison to their allyl analogs. Due to significant differences in the activity of the compounds, molecular modeling was performed, which was aimed at comparing the interactions between 11ß-HSD1 and ligands differing by substituent at the amine group (allyl vs. methyl). Modeling showed that the absence of the allyl group can lead to the rotation of whole ligand molecule which affects its interaction with the enzyme.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Inibidores Enzimáticos/síntese química , Tiazóis/química , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Sítios de Ligação , Inibidores Enzimáticos/metabolismo , Humanos , Ligantes , Simulação de Acoplamento Molecular , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/química , Isoformas de Proteínas/metabolismo , Estrutura Terciária de Proteína , Relação Estrutura-Atividade , Tiazóis/metabolismo
4.
Nat Prod Res ; 33(21): 3083-3088, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30427740

RESUMO

A new protostane-type triterpenoid bearing an oxetane ring in the side-chain, named alisol W (1), has been obtained from the dried rhizome of Alisma plantago-aquatica subsp. orientale. The structure and absolute configuration of compound 1 was determined from extensive spectroscopic analysis. In addition, the vasorelaxant activity and the inhibition on 11ß-HSD1 of compound 1 were also evaluated, however, it didn't show remarkable effects.


Assuntos
Alisma/química , Triterpenos/isolamento & purificação , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Humanos , Estrutura Molecular , Rizoma/química , Análise Espectral , Triterpenos/química , Vasodilatadores/análise
6.
J Mol Cell Cardiol ; 125: 106-116, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30291912

RESUMO

BACKGROUND: High-fat diet (HFD) induces cardiac hypertrophy; however, the underlying cellular and molecular mechanisms are yet unclear. In the present study, we investigated the roles of 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1), an amplifier of local glucocorticoid activity, in the pathogenesis of cardiac dysfunction. METHODS: Male Wistar rats were fed normal chow diet (NC) or HFD and examined the cardiac remolding and functional alteration by echocardiography and histology. Primary neonatal rat ventricular cardiomyocytes (NRCMs) treated with palmitic acid (PA) or infected by lentivirus were used for identifying the role by 11ß-HSD1 in cardiac hypertrophy. Genome microarray of NRCMs was performed to further reveal the mechanism underlying cardiac dysfunction. RESULTS: Palmitic acid induced hypertrophy in NRCMs that upregulated 11ß-HSD1 expression in cardiomyocytes, which led to a significant enlargement in the cell size and expression of cardiac hypertrophy-specific genes. Conversely, a remarkable decrease in cardiomyocytes size was detected in either BVT.2733 (a selective inhibitor of 11ß-HSD1)-treated or 11ß-HSD1-deficient NRCMs. Furthermore, both glucocorticoid receptor (GR) antagonist RU486 and mineralocorticoid receptor (MR) antagonist spironolactone markedly attenuated the 11ß-HSD1-induced cardiomyocytes hypertrophy. Genome microarray revealed that cAMP and calcium signaling pathways are potential downstream signaling pathways regulated by 11ß-HSD1 in cardiomyocytes hypertrophy. Similar to in vitro results, BVT.2733 strikingly attenuated cardiac hypertrophy and improved cardiac function in HFD-fed rats. CONCLUSION: 11ß-HSD1 acts as an important regulator that controls the cardiac remolding via both GR and MR and the pharmacological inhibition of 11ß-HSD1 could be a new therapeutic approach in preventing HFD-induced cardiac hypertrophy.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Cardiomiopatias/tratamento farmacológico , Cardiomiopatias/metabolismo , Dieta Hiperlipídica/efeitos adversos , Animais , Animais Recém-Nascidos , Sinalização do Cálcio/efeitos dos fármacos , Cardiomiopatias/etiologia , Teste de Tolerância a Glucose , Masculino , Mifepristona/farmacologia , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Ácido Palmítico/farmacologia , Ratos , Ratos Wistar , Receptores de Glucocorticoides/antagonistas & inibidores , Receptores de Glucocorticoides/metabolismo , Receptores de Mineralocorticoides/metabolismo , Espironolactona/farmacologia
7.
Bioorg Med Chem ; 26(18): 5128-5139, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30245006

RESUMO

The enzyme 11ß-HSD1 plays a crucial role in the tissue-specific regulation of cortisol levels and it has been associated with various diseases. Inhibition of 11ß-HSD1 is an attractive intervention strategy and the discovery of novel selective 11ß-HSD1 inhibitors is of high relevance. In this study, we identified and evaluated a new series of selective peptide 11ß-HSD1 inhibitors with potential for skin care applications. This novel scaffold was designed with the aid of molecular modeling and two previously reported inhibitors. SAR optimization yielded highly active peptides (IC50 below 400 nM) that were inactive at 1 µM concentration against structurally related enzymes (11ß-HSD2, 17ß-HSD1 and 17ß-HSD2). The best performing peptides inhibited the conversion of cortisone into cortisol in primary human keratinocytes and the most active compound, 5d, was further shown to reverse cortisone-induced collagen damage in human ex-vivo tissue.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Desenho de Drogas , Inibidores Enzimáticos/farmacologia , Peptídeos/farmacologia , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Modelos Moleculares , Estrutura Molecular , Peptídeos/síntese química , Peptídeos/química , Relação Estrutura-Atividade
8.
Pharmacology ; 102(3-4): 169-179, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30099452

RESUMO

In this study, rat and human 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) have been cloned by lentiviral transduction and expressed by CHO-K1 cells. The results showed that recombinant plasmids contained R11bhsd1 or H11bhsd1 have been constructed, which is consistent with the gene bank respectively. A clone cell was selected with G418 and cultivated to express 11ß-HSD1. 11ß-HSD1 catalytic activity of rat and human were 99.5 and 98.7%, respectively, determined by scanning radiometer. And the cloned CHO-K1 cells expressed the protein of 11ß-HSD1 in a long-term and stable manner, which makes it suitable for screening 11ß-HSD1 inhibitor. The three-dimensional structure of 11ß-HSD1 was used for studying the interaction between inhibitor and enzyme by the binding poses predicted by AutoDock and LeDock software. The docking results revealed that compound 8 forms 2 hydrogen bonds with the residues of Gly-216 and Ile-218 in 11ß-HSD1, that is to say compound 8 maybe a good 11ß-HSD1 inhibitor. Moreover, C57BL/6 mice with R11bHsd1 overexpression had a higher body weight, glucose, total cholesterol, and triglyceride levels compared to the mice treated with an empty viral vector. The results might provide a beneficial foundation for selecting inhibitors of 11ß-HSD1 or for researching drug candidate mechanisms.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Curcumina/análogos & derivados , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/química , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/genética , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Animais , Células CHO , Clonagem Molecular , Cricetinae , Cricetulus , Curcumina/síntese química , Curcumina/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Inibidores Enzimáticos/síntese química , Lentivirus/genética , Fígado/patologia , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Transdução Genética
9.
Eur J Pharmacol ; 835: 169-178, 2018 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-30096297

RESUMO

11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) is a cortisol regenerating enzyme that amplifies tissue glucocorticoid levels, especially in the liver and adipose tissue. Knockout mice or a selective inhibitor of 11ß-HSD1 improves metabolic syndrome parameters in preclinical models and human clinical trials. Here, we evaluated the therapeutic potential of INU-101, a potent and selective oral inhibitor of 11ß-HSD1. The in vitro activity of 11ß-HSD1 was measured using the homogeneous time-resolved fluorescence (HTRF) assay. Differentiated adipocytes were used to evaluate the cellular 11ß-HSD1 activity. To determine the inhibitory effects on 11ß-HSD1 in tissues, we performed ex vivo studies using liver and adipose tissue isolated from C57BL/6 J mice and Cynomolgus monkeys. KKAy mice, ob/ob mice and ZDF rats were administered INU-101 to evaluate whether this compound ameliorated metabolic abnormalities in obese and diabetic animals. INU-101 had highly potent inhibitory activity in mouse, monkey and human 11ß-HSD1, derived from liver microsomes. The oral administration of INU-101 significantly inhibited 11ß-HSD1 activity in the liver and adipose tissue of mice and monkeys. In KKAy mice, ob/ob mice and ZDF rats, the oral administration of INU-101 enhanced insulin sensitivity and lowered the fasting blood glucose level. Furthermore, INU-101 treatment decreased the body weight and ameliorated an improved lipid profile in the diabetic mouse model. These results suggest that the 11ß-HSD1 inhibitor, INU-101 may serve as a novel drug candidate for the treatment of type 2 diabetes and metabolic syndrome.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Adamantano/análogos & derivados , Adamantano/farmacologia , Inibidores Enzimáticos/farmacologia , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/química , Células 3T3-L1 , Adamantano/química , Adamantano/farmacocinética , Animais , Peso Corporal/efeitos dos fármacos , Humanos , Camundongos , Modelos Moleculares , Conformação Proteica , Ratos
10.
Br J Pharmacol ; 175(19): 3784-3796, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30006998

RESUMO

BACKGROUND AND PURPOSE: Glucocorticoids are a major class of stress hormones known to participate in stress-induced hyperalgesia. Although 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1) is a key enzyme in the intracellular regeneration of glucocorticoids in the CNS, its role in pain perception has not been assessed. Here, we examined the effects of ASP3662, a novel 11ß-HSD1 inhibitor, on neuropathic and dysfunctional pain. EXPERIMENTAL APPROACH: The enzyme inhibitory activities and pharmacokinetics of ASP3662 were examined, and its antinociceptive effects were evaluated in models of neuropathic pain, fibromyalgia and inflammatory pain in Sprague-Dawley rats. KEY RESULTS: ASP3662 inhibited human, mouse and rat 11ß-HSD1 but not human 11ß-HSD2, in vitro. ASP3662 had no significant effect on 87 other possible targets (enzymes, transporters and receptors). ASP3662 inhibited in vitro conversion of glucocorticoid from its inactive to active form in extracts of rat brain and spinal cord. Pharmacokinetic analysis in Sprague-Dawley rats showed that ASP3662 has CNS-penetrability and long-lasting pharmacokinetic properties. Single oral administration of ASP3662 ameliorated mechanical allodynia in spinal nerve ligation (SNL) and streptozotocin-induced diabetic rats and thermal hyperalgesia in chronic constriction nerve injury rats. ASP3662 also restored muscle pressure thresholds in reserpine-induced myalgia rats. Intrathecal administration of ASP3662 was also effective in SNL rats. However, ASP3662 had no analgesic effects in adjuvant-induced arthritis rats. CONCLUSIONS AND IMPLICATIONS: ASP3662 is a potent, selective and CNS-penetrable inhibitor of 11ß-HSD1. The effects of ASP3662 suggest that selective inhibition of 11ß-HSD1 may be an attractive approach for the treatment of neuropathic and dysfunctional pain, as observed in fibromyalgia.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Analgésicos/farmacologia , Benzamidas/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Dor/tratamento farmacológico , Triazóis/farmacologia , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Administração Oral , Analgésicos/administração & dosagem , Analgésicos/química , Animais , Benzamidas/administração & dosagem , Benzamidas/química , Diabetes Mellitus Experimental/induzido quimicamente , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Masculino , Dor/induzido quimicamente , Ratos , Ratos Sprague-Dawley , Estreptozocina/antagonistas & inibidores , Relação Estrutura-Atividade , Triazóis/administração & dosagem , Triazóis/química
11.
BMC Pharmacol Toxicol ; 19(1): 45, 2018 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-30021644

RESUMO

BACKGROUND: Nonylphenol (NP) is an environmental endocrine-disrupting chemical (EDC) detected in human cord blood and milk. NP exposure in developmental periods results in hyperadrenalism and increasing 11ß-hydroxysteroid dehydrogenase I (11ß-HSD1) activity in an adult rat model. Alleviating 11ß-HSD1 activity is therefore a logical and common way to treat hyperadrenalism. PF915275 (PF; 4'-cyano-biphenyl-4-sulfonic acid (6-amino-pyridin-2-yl)-amide) is a selective inhibitor for 11ß-HSD1. This study aimed to determine whether PF915275 could alleviate the hyperadrenalism induced by NP. In addition to a rat model, the effects of NP and PF915275 were measured in human preadipocytes. METHODS: For the in vivo rat model, female adult rats exposed to NP during the developmental period were divided into two treatment groups, with one receiving oral DMSO solution and the other receiving PF915275 once per day for 4 weeks. After the final treatment, the rats from each group were sacrificed for analysis. For the in vitro human model, human preadipocytes received 2 regimens of NP treatment. One treatment regimen occurred before differentiation (to mimic the sensitive developmental period; P exposure), and the other included continuous exposure from preadipocytes to fully differentiated adipocytes (to mimic the growing and adult periods, respectively; C exposure). Protein and RNA were extracted from rat tissues and the preadipocytes for western blot and real-time PCR analysis. RESULTS: In the rat model, PF915275 alleviated NP-induced effects by interfering with adipogenesis pathways, including enhancing PPARα expression, decreasing PPARγ expression, and reducing both 11ß-HSD1 protein and mRNA expression levels. Additionally, PF915275 reduced the effects of the adrenal corticoid synthesis pathway by reducing StAR expression and 11ß-hydroxylase and aldosterone synthase activities. With short-term exposure, NP enhanced PPARγ and FASN mRNA expression levels and reduced PPARα expression, whereas PF915275 alleviated these effects. With C exposure, the NP-induced accumulation of intracellular lipids was reduced by PF915275 treatment, which was mediated by decreased PPARγ mRNA and protein expression levels and increased PPARα protein expression. CONCLUSIONS: The effects of NP and PF915275 treatment in both rat and human cell models are similar. Rats may be an appropriate model to study the effects of NP in humans, especially during the developmental period.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Adiposidade/efeitos dos fármacos , Hiperfunção Adrenocortical/induzido quimicamente , Hiperfunção Adrenocortical/tratamento farmacológico , Aminopiridinas/uso terapêutico , Fenóis , Sulfonamidas/uso terapêutico , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/genética , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Hiperfunção Adrenocortical/metabolismo , Aldosterona/sangue , Aminopiridinas/farmacologia , Animais , Células Cultivadas , Corticosterona/sangue , Ácido Graxo Sintase Tipo I/genética , Ácido Graxo Sintase Tipo I/metabolismo , Feminino , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , PPAR alfa/genética , PPAR alfa/metabolismo , PPAR gama/genética , PPAR gama/metabolismo , Gravidez , Ratos Sprague-Dawley , Sulfonamidas/farmacologia
12.
Molecules ; 23(6)2018 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-29899225

RESUMO

Plant extracts from the genus Cecropia have been used by Latin-American traditional medicine to treat metabolic disorders and diabetes. Previous results have shown that roots of Cecropia telenitida contain pentacyclic triterpenes and these molecules display a hypoglycemic effect in an insulin-resistant murine model. The pharmacological target of these molecules, however, remains unknown. Several lines of evidence indicate that pentacyclic triterpenes inhibit the 11ß-hydroxysteroid dehydrogenase type 1 enzyme, which highlights the potential use of this type of natural product as phytotherapeutic or botanical dietary supplements. The main goal of the study was the evaluation of the inhibitory effect of Cecropia telenitida molecules on 11ß-hydroxysteroid dehydrogenase type 1 enzyme activity. A pre-fractionated chemical library was obtained from the roots of Cecropia telenitida using several automated chromatography separation steps and a homogeneous time resolved fluorescence assay was used for the bio-guided isolation of inhibiting molecules. The screening of a chemical library consisting of 125 chemical purified fractions obtained from Cecropia telenitida roots identified one fraction displaying 82% inhibition of the formation of cortisol by the 11ß-hydroxysteroid dehydrogenase type 1 enzyme. Furthermore, a molecule displaying IC50 of 0.95 ± 0.09 µM was isolated from this purified fraction and structurally characterized, which confirms that a pentacyclic triterpene scaffold was responsible for the observed inhibition. Our results support the hypothesis that pentacyclic triterpene molecules from Cecropia telenitida can inhibit 11ß-hydroxysteroid dehydrogenase type 1 enzyme activity. These findings highlight the potential ethnopharmacological use of plants from the genus Cecropia for the treatment of metabolic disorders and diabetes.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Triterpenos Pentacíclicos/farmacologia , Urticaceae/química , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Ensaios de Triagem em Larga Escala , Humanos , Medicina Tradicional , Estrutura Molecular , Triterpenos Pentacíclicos/química , Triterpenos Pentacíclicos/isolamento & purificação , Extratos Vegetais/química , Raízes de Plantas/química , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/isolamento & purificação , Bibliotecas de Moléculas Pequenas/farmacologia
13.
Bioorg Chem ; 79: 115-121, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29738970

RESUMO

11ß-Hydroxysteroid dehydrogenase type 1 (11ß-HSD1) is an enzyme that catalyzes the conversion of inactive cortisone into physiologically active cortisol. Inhibiting the activity of this enzyme plays a key role in the treatment of Cushing's syndrome, metabolic syndrome and type 2 diabetes. Therefore, new compounds that are selective inhibitors of this enzyme are constantly being looked for. In this work we present the synthesis of 2-(allylamino)thiazol-4(5H)-one derivatives by the reaction of N-allylthiourea with appropriate α-bromoesters. In the case of using of aliphatic α-bromoesters and α-bromo-ß-phenylesters, the reactions were carried out in a basic medium (sodium ethoxide) and the products were isolated with a yield of up to 68%. Derivatives containing spiro systems in which carbon C-5 of the thiazole ring is the linker atom were obtained in the presence of N,N-diisopropylethylamine. Some of the obtained compounds, at a concentration of 10 µM have activity in the inhibition of 11ß-HSD1 up to 71%. IC50 value for the most active compound: 2-(allylamino)-1-thia-3-azaspiro[4.5]dec-2-en-4-one is 2.5 µM. With a high degree of 11ß-HSD1 inhibition and a relatively large difference in the inhibition of 11ß-HSD1 and 11ß-HSD2 activity, this compound appears to be promising and should be subjected to further testing.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Tiazóis/farmacologia , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/química , Sítios de Ligação , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Tiazóis/síntese química , Tiazóis/química
14.
Mol Neurobiol ; 55(12): 8904-8915, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29611102

RESUMO

Elevated glucocorticoid (GC) exposure is widely accepted as a key factor in the age-related cognitive decline in rodents and humans. 11ß-HSD1 is a key enzyme in the GCs pathway, catalyzing the conversion of 11ß-dehydrocorticosterone to corticosterone in mice, with possible implications in neurodegenerative processes and cognitive impairment. Here, we determined the effect of a new 11ß-HSD1 inhibitor, RL-118, administered to 12-month-old senescence-accelerated mouse-prone 8 (SAMP8) mice with neuropathological AD-like hallmarks and widely used as a rodent model of cognitive dysfunction. Behavioral tests (open field and object location) and neurodegeneration molecular markers were studied. After RL-118 treatment, increased locomotor activity and cognitive performance were found. Likewise, we found changes in hippocampal autophagy markers such as Beclin1, LC3B, AMPKα, and mTOR, indicating a progression in the autophagy process. In line with autophagy increase, a diminution in phosphorylated tau species (Ser 396 and Ser 404) jointly with an increase in ADAM10 and sAPPα indicated that an improvement in removing the abnormal proteins by autophagy might be implicated in the neuroprotective role of the 11ß-HSD1 inhibitor. In addition, gene expression of oxidative stress (OS) and inflammatory markers, such as Hmox1, Aldh2, Il-1ß, and Ccl3, were reduced in old treated mice in comparison to that of the control group. Consistent with this, we further demonstrate a significant correlation with autophagy markers and cognitive improvement and significant inverse correlation with autophagy, OS, and neuroinflammation markers. We concluded that inhibition of 11ß-HSD1 by RL-118 prevented neurodegenerative processes and cognitive decline, acting on autophagy process, being an additional neuroprotective mechanism not described previously.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Autofagia/efeitos dos fármacos , Cognição/efeitos dos fármacos , Inflamação/patologia , Estresse Oxidativo/efeitos dos fármacos , Piperidonas/farmacologia , Piridinas/farmacologia , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Animais , Ansiedade/patologia , Ansiedade/fisiopatologia , Proteína Beclina-1/metabolismo , Biomarcadores/metabolismo , Modelos Animais de Doenças , Feminino , Memória/efeitos dos fármacos , Camundongos , Camundongos Mutantes Neurológicos , Proteínas Associadas aos Microtúbulos/metabolismo , Modelos Biológicos , Degeneração Neural/patologia , Degeneração Neural/fisiopatologia , Serina-Treonina Quinases TOR/metabolismo
15.
Molecules ; 23(3)2018 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-29495550

RESUMO

We recently found that a cyclohexanecarboxamide derived from 4-azatetracyclo[5.3.2.02,6.08,10]dodec-11-ene displayed low nanomolar inhibition of 11ß-HSD1. In continuation of our efforts to discover potent and selective 11ß-HSD1 inhibitors, herein we explored several replacements for the cyclohexane ring. Some derivatives exhibited potent inhibitory activity against human 11ß-HSD1, although with low selectivity over the isoenzyme 11ß-HSD2, and poor microsomal stability.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Técnicas de Química Sintética , Desenho de Drogas , Ativação Enzimática , Inibidores Enzimáticos/síntese química , Humanos , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Relação Estrutura-Atividade
16.
Drug Metab Dispos ; 46(6): 770-778, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29514826

RESUMO

BI 187004, an 11ß-hydroxysteroid dehydrogenase 1 inhibitor, was administered once daily for 14 days to eight patients with type 2 diabetes mellitus. N-methylation was identified as a major biotransformation pathway. In four patients treated with BI 187004, the plasma exposure of an N-methylbenzimidazole metabolite [N-methylbenzimidazole regioisomer 1 (M1)] was 7-fold higher than the remaining four patients, indicating a substantial degree of metabolic variation. To identify the methyltransferase enzymes responsible for N-methylation, BI 187004 was incubated with human liver microsomes (HLM), human kidney microsomes (HKM), and their respective cytosolic preparations in the presence and absence of isoform-selective chemical inhibitors. Additionally, BI 187004 was incubated with several human recombinant methyltransferases: catechol O-methyltransferase (rhCOMT), histamine N-methyltransferase (rhHNMT), nicotinamide N-methyltransferase (rhNNMT), glycine N-methyltransferase (rhGNMT), and thiopurine S-methyltransferase (rhTPMT). M1 was principally observed in HLM and HKM incubations, minimally formed in liver and kidney cytosol, and not formed during incubations with recombinant methyltransferase enzymes. In all microsomal and cytosolic incubations, the formation of M1 was inhibited only by 2,3-dichloro-α-methylbenzylamine (DCMB), an inhibitor of thiol S-methyltransferase (TMT), providing evidence that TMT catalyzed the formation of M1. Interestingly, the N-methylbenzimidazole regioisomer (M14) was only observed in vitro, predominantly during incubations with human kidney cytosol and rhHNMT. The formation of M14 was inhibited by amodiaquine (an HNMT inhibitor) and DCMB, providing additional evidence that both HNMT and TMT catalyzed M14 formation. Overall, using BI 187004 as a substrate, this study demonstrates a novel TMT-mediated N-methylation biotransformation and an HNMT-mediated regioselective N-methylation.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Metiltransferases/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biotransformação/fisiologia , Criança , Pré-Escolar , Citosol/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Humanos , Rim/metabolismo , Fígado/metabolismo , Masculino , Metilação , Microssomos Hepáticos/metabolismo , Pessoa de Meia-Idade , Proteínas Recombinantes/metabolismo , Compostos de Sulfidrila , Adulto Jovem
17.
J Pharm Sci ; 107(6): 1633-1641, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29458062

RESUMO

Degradation of an active pharmaceutical ingredient (API), a 2-(3-(1-(4-chlorophenyl)cyclopropyl)-[1,2,4]triazolo[4,3-a]pyridin-8-yl)propan-2-ol hydrochloride salt, was observed in a capsule formulation stressed at 50°C or 40°C/75% relative humidity conditions for 1 month. Two unknown degradants were identified as cationic pseudodimers of the API via accurate mass liquid chromatography-mass spectrometry and 1- and 2-dimensional NMR analyses. A plausible degradation pathway of the API was postulated which led to the identification of 2 key N-oxide degradants in the stressed capsule formulation at trace levels. It was hypothesized that the N-oxide degradants could be protonated and undergo further transformation so as to react with another API free base to form pseudodimeric N-oxide intermediates, followed by protonation/dehydration to yield the cationic pseudodimers of the API. The proposed degradation pathway was further supported by formulation screening studies: (1) the removal of magnesium stearate (base/lubricant) from the formulation to reduce the formation of API free base, which is susceptible to oxidation to form N-oxides; (2) the replacement of API hydrochloride salt by its free base form to eliminate the proton source for protonation of the N-oxides so as to prevent their further transformation; and (3) the addition of anti-oxidants to minimize the oxidation of API free base to N-oxides.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Inibidores Enzimáticos/química , Piridinas/química , Triazóis/química , Cápsulas , Estabilidade de Medicamentos , Excipientes/química , Oxirredução
18.
Steroids ; 132: 25-32, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29425740

RESUMO

Many flavonoids and isoflavonoids have anti-diabetic effects in animal models. However, the mechanisms that are involved are generally unclear. Since 11ß-hydroxysteroid dehydrogenases (HSD11Bs) play important roles in diabetes, we hypothesize that flavonoids and isoflavonoids may affect diabetes by targeting two isoforms of HSD11B differently. The inhibitory effects of flavonoids (apigenin and quercetin) and isoflavonoids [genistein and (±) equol] on rat and human HSD11B1 and HSD11B2 were analyzed. The potencies of inhibition on human HSD11B1 reductase was in the order of apigenin > quercetin > genistein > (±) equol, with IC50 values of 2.19, 5.36, 11.00, and over 100 µM, respectively. Genistein also inhibited rat HSD11B1 reductase with IC50 value of 24.58 µM, while other three chemicals showed no effects on the enzyme activity with IC50 values over 100 µM. However, apigenin and (±) equol did not inhibit human HSD11B2 at concentrations as high as 100 µM, while genistein and quercetin inhibited human HSD11B2 by 60% and 50% at 100 µM, respectively. The effective flavonoids and isoflavonoids are noncompetitive inhibitors of HSD11B1 when steroid substrates were used. Docking analysis showed that they bound to the steroid-binding site of the human HSD11B1. These data indicate that apigenin is a selective inhibitor of human HSD11B1 of two HSD11B isoforms, which may be useful in managing symptoms of the metabolic syndrome.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Flavonoides/farmacologia , Isoflavonas/farmacologia , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/química , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/química , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/metabolismo , Animais , Apigenina/metabolismo , Apigenina/farmacologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/metabolismo , Equol/farmacologia , Flavonoides/metabolismo , Genisteína/farmacologia , Humanos , Isoflavonas/metabolismo , Simulação de Acoplamento Molecular , Conformação Proteica , Quercetina/metabolismo , Quercetina/farmacologia , Ratos
19.
J Neuroendocrinol ; 30(3): e12580, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29418022

RESUMO

The hypothalamus is the regulatory centre of both appetite and energy balance and endoplasmic reticulum (ER) stress in the hypothalamus is involved in the pathogenesis of obesity. Recently, inhibition of 11 ß hydroxysteroid dehydrogenase type1 (11ß-HSD1) was reported to have an anti-obesity effect by reducing fat mass. However, the link between the role of 11ß-HSD1 in the hypothalamus and obesity has yet to be determined. In the present study, embryonal primary hypothalamic neurones and high-fat diet (HFD) fed mice were used to investigate the anorexigenic effects of 11ß-HSD1 inhibitors both in vitro and in vivo. In hypothalamic neurones, carbenoxolone (a non selecitve 11ß-HSD inhibitor) alleviated ER stress and ER stress-induced neuropeptide alterations. In HFD mice, i.c.v. administration of carbenoxolone or KR67500 (nonselective and selective 11ß-HSD1 inhibitors, respectively) was associated with less weight gain compared to control mice for 24 hours after treatment, presumably by reducing food intake. Furthermore, glucose regulated protein (Grp78), spliced X-box binding protein (Xbp-1s), c/EBP homologous protein (chop) and ER DnaJ homologue protein (Erdj4) expression was decreased in the hypothalami of mice administrated 11ß-HSD1 inhibitors compared to controls. Conversely, the phosphorylation of protein kinase B (PKB/Akt), signal transducer and activator of transcription 3 (Stat3), mitogen-activated protein kinase (MAPK/ERK) and S6 kinase1 (S6K1) in the hypothalamus was induced more in mice treated using the same regimes. In conclusion, acute 11ß-HSD1 inhibition in the hypothalamus could reduce food intake by decreasing ER stress and increasing insulin, leptin, and mammalian target of rapamycin complex 1 (mTORC1) signalling.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Fármacos Antiobesidade/uso terapêutico , Carbenoxolona/uso terapêutico , Dieta Hiperlipídica , Ingestão de Alimentos/efeitos dos fármacos , Obesidade/tratamento farmacológico , Animais , Fármacos Antiobesidade/administração & dosagem , Peso Corporal/efeitos dos fármacos , Carbenoxolona/administração & dosagem , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Proteínas de Choque Térmico/metabolismo , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Injeções Intraventriculares , Insulina/metabolismo , Leptina/metabolismo , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Glicoproteínas de Membrana/metabolismo , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Obesidade/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína 1 de Ligação a X-Box/metabolismo
20.
Mol Pharm ; 15(3): 831-839, 2018 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-29337562

RESUMO

When medicinal chemists need to improve oral bioavailability (%F) during lead optimization, they systematically modify compound properties mainly based on their own experience and general rules of thumb. However, at least a dozen properties can influence %F, and the difficulty of multiparameter optimization for such complex nonlinear processes grows combinatorially with the number of variables. Furthermore, strategies can be in conflict. For example, adding a polar or charged group will generally increase solubility but decrease permeability. Identifying the 2 or 3 properties that most influence %F for a given compound series would make %F optimization much more efficient. We previously reported an adaptation of physiologically based pharmacokinetic (PBPK) simulations to predict %F for lead series from purely computational inputs within a 2-fold average error. Here, we run thousands of such simulations to generate a comprehensive "bioavailability landscape" for each series. A key innovation was recognition that the large and variable number of p Ka's in drug molecules could be replaced by just the two straddling the isoelectric point. Another was use of the ZINC database to cull out chemically inaccessible regions of property space. A quadratic partial least squares regression (PLS) accurately fits a continuous surface to these thousands of bioavailability predictions. The PLS coefficients indicate the globally sensitive compound properties. The PLS surface also displays the %F landscape in these sensitive properties locally around compounds of particular interest. Finally, being quick to calculate, the PLS equation can be combined with models for activity and other properties for multiobjective lead optimization.


Assuntos
Química Farmacêutica/métodos , Descoberta de Drogas/métodos , Inibidores Enzimáticos/farmacocinética , Modelos Biológicos , Relação Quantitativa Estrutura-Atividade , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Administração Oral , Disponibilidade Biológica , Simulação por Computador , Conjuntos de Dados como Assunto , Absorção Intestinal , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Distribuição Tecidual
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