12 results on '"11β-HSD1"'
Search Results
2. Biopharmaceutical Characterization and Bioavailability Study of a Tetrazole Analog of Clofibric Acid in Rat.
- Author
-
Vara-Gama, Nancy, Valladares-Méndez, Adriana, Navarrete-Vazquez, Gabriel, Estrada-Soto, Samuel, Manuel Orozco-Castellanos, Luis, and César Rivera-Leyva, Julio
- Subjects
- *
TETRAZOLES , *DRUG bioavailability , *CLOFIBRIC acid , *BIOPHARMACEUTICS , *PHARMACOKINETICS - Abstract
In the current investigation, the physicochemical, biopharmaceutical and pharmacokinetic characterization of a new clofibric acid analog (Compound 1) was evaluated. Compound 1 showed affinity by lipophilic phase in 1 to 5 pH interval, indicating that this compound would be absorbed favorably in duodenum or jejunum. Also, Compound 1 possess two ionic species, first above of pH 4.43 and, the second one is present over pH 6.08. The apparent permeability in everted sac rat intestine model was 8.73 × 10−6 cm/s in duodenum and 1.62 × 10−5 cm/s in jejunum, suggesting that Compound 1 has low permeability. Elimination constant after an oral administration of 50 μg/kg in Wistar rat was 1.81 h−1, absorption constant was 3.05 h−1, Cmax was 3.57 μg/mL at 0.33 h, AUC0–α was 956.54 μ/mL·h and distribution volume was 419.4 mL. To IV administration at the same dose, ke was 1.21 h−1, Vd was 399.6 mL and AUC0–α was 747.81 μ/mL·h. No significant differences were observed between pharmacokinetic parameters at every administration route. Bioavailability evaluated was 10.4%. Compound 1 is metabolized to Compound 2 probably by enzymatic hydrolysis, and it showed a half-life of 9.24 h. With these properties, Compound 1 would be considered as a prodrug of Compound 2 with potential as an antidiabetic and anti dyslipidemic agent. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
3. A New Triterpenoid from Teucrium viscidum
- Author
-
Yonghui Zhang, Yanyan Si, Guangmin Yao, Zengwei Luo, Yongbo Xue, Guangxin Xia, Xincai Hao, and Jinwen Zhang
- Subjects
Teucrium viscidum ,triterpenoids ,lignans ,11β-HSD1 ,Organic chemistry ,QD241-441 - Abstract
A new ursane-type triterpenoid, 3β-hydroxy-urs-30-p-Z-hydroxycinnamoyloxy-12-en-28-oic-acid (1), together with three known triterpenoids, 3β-hydroxy-urs-30-p-E-hydroxycinnamoyloxy-12-en-28-oic-acid (2), 2α,3β,19α-trihydroxy-urs-12-en-28-oic-acid (3), and ursolic acid (4), four known lignans, pinoresinol (5), 9α-hydroxypinoresinol (6), (+)-medioresinol (7), and (+)-kobusin (8), and two steroids, β-sitosterol (9), and daucosterol (10), were isolated from the whole parts of Teucrium viscidum. Their structures were established by a combination of spectroscopic data analysis, besides comparison with literature data. Compounds 1–4 were evaluated for their inhibitory activities against 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1).
- Published
- 2013
- Full Text
- View/download PDF
4. Pentacyclic Triterpenes from Cecropia telenitida Can Function as Inhibitors of 11β-Hydroxysteroid Dehydrogenase Type 1
- Author
-
Catalina Mosquera, Aram J. Panay, and Guillermo Montoya
- Subjects
BDS ,botanical dietary supplement ,PT ,pentacyclic triterpene ,HTRF ,homogeneous time resolved fluorescence ,11β-HSD1 ,11-β hydroxysteroid dehydrogenase type 1 ,CBX ,carbenoxolone ,Organic chemistry ,QD241-441 - Abstract
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 11β-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 11β-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 11β-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 11β-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.
- Published
- 2018
- Full Text
- View/download PDF
5. Exploring N-acyl-4-azatetracyclo[5.3.2.02,6.08,10]dodec-11-enes as 11β-HSD1 Inhibitors
- Author
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Rosana Leiva, Andrew McBride, Margaret Binnie, Scott P. Webster, and Santiago Vázquez
- Subjects
drug discovery ,enzyme inhibitors ,polycyclic hydrocarbons ,SAR investigation ,11β-HSD1 ,Organic chemistry ,QD241-441 - Abstract
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 11β-HSD1. In continuation of our efforts to discover potent and selective 11β-HSD1 inhibitors, herein we explored several replacements for the cyclohexane ring. Some derivatives exhibited potent inhibitory activity against human 11β-HSD1, although with low selectivity over the isoenzyme 11β-HSD2, and poor microsomal stability.
- Published
- 2018
- Full Text
- View/download PDF
6. Biopharmaceutical Characterization and Bioavailability Study of a Tetrazole Analog of Clofibric Acid in Rat
- Author
-
Nancy Vara-Gama, Adriana Valladares-Méndez, Gabriel Navarrete-Vazquez, Samuel Estrada-Soto, Luis Manuel. Orozco-Castellanos, and Julio César Rivera-Leyva
- Subjects
diabetes ,bioavailability ,clofibric acid ,11β-HSD1 ,tetrazole ,dyslipidemia ,Organic chemistry ,QD241-441 - Abstract
In the current investigation, the physicochemical, biopharmaceutical and pharmacokinetic characterization of a new clofibric acid analog (Compound 1) was evaluated. Compound 1 showed affinity by lipophilic phase in 1 to 5 pH interval, indicating that this compound would be absorbed favorably in duodenum or jejunum. Also, Compound 1 possess two ionic species, first above of pH 4.43 and, the second one is present over pH 6.08. The apparent permeability in everted sac rat intestine model was 8.73 × 10−6 cm/s in duodenum and 1.62 × 10−5 cm/s in jejunum, suggesting that Compound 1 has low permeability. Elimination constant after an oral administration of 50 μg/kg in Wistar rat was 1.81 h−1, absorption constant was 3.05 h−1, Cmax was 3.57 μg/mL at 0.33 h, AUC0–α was 956.54 μ/mL·h and distribution volume was 419.4 mL. To IV administration at the same dose, ke was 1.21 h−1, Vd was 399.6 mL and AUC0–α was 747.81 μ/mL·h. No significant differences were observed between pharmacokinetic parameters at every administration route. Bioavailability evaluated was 10.4%. Compound 1 is metabolized to Compound 2 probably by enzymatic hydrolysis, and it showed a half-life of 9.24 h. With these properties, Compound 1 would be considered as a prodrug of Compound 2 with potential as an antidiabetic and anti dyslipidemic agent.
- Published
- 2017
- Full Text
- View/download PDF
7. Molecular Modeling Studies of 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors through Receptor-Based 3D-QSAR and Molecular Dynamics Simulations
- Author
-
Haiyan Qian, Jiongjiong Chen, Youlu Pan, and Jianzhong Chen
- Subjects
11β-HSD1 ,3D-QSAR ,MESP ,MD simulations ,binding free energy ,Organic chemistry ,QD241-441 - Abstract
11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is a potential target for the treatment of numerous human disorders, such as diabetes, obesity, and metabolic syndrome. In this work, molecular modeling studies combining molecular docking, 3D-QSAR, MESP, MD simulations and free energy calculations were performed on pyridine amides and 1,2,4-triazolopyridines as 11β-HSD1 inhibitors to explore structure-activity relationships and structural requirement for the inhibitory activity. 3D-QSAR models, including CoMFA and CoMSIA, were developed from the conformations obtained by docking strategy. The derived pharmacophoric features were further supported by MESP and Mulliken charge analyses using density functional theory. In addition, MD simulations and free energy calculations were employed to determine the detailed binding process and to compare the binding modes of inhibitors with different bioactivities. The binding free energies calculated by MM/PBSA showed a good correlation with the experimental biological activities. Free energy analyses and per-residue energy decomposition indicated the van der Waals interaction would be the major driving force for the interactions between an inhibitor and 11β-HSD1. These unified results may provide that hydrogen bond interactions with Ser170 and Tyr183 are favorable for enhancing activity. Thr124, Ser170, Tyr177, Tyr183, Val227, and Val231 are the key amino acid residues in the binding pocket. The obtained results are expected to be valuable for the rational design of novel potent 11β-HSD1 inhibitors.
- Published
- 2016
- Full Text
- View/download PDF
8. A New Triterpenoid from Teucrium viscidum.
- Author
-
Xincai Hao, Jinwen Zhang, Guangxin Xia, Yongbo Xue, Zengwei Luo, Yanyan Si, Guangmin Yao, and Yonghui Zhang
- Subjects
- *
TRITERPENOIDS , *URSOLIC acid , *STEROIDS , *SPECTRUM analysis , *LIGNANS , *DEHYDROGENASES - Abstract
A new ursane-type triterpenoid, 3β-hydroxy-urs-30-p-Z-hydroxycinnamoyloxy- 12-en-28-oic-acid (1), together with three known triterpenoids, 3β-hydroxy-urs-30-p-Ehydroxycinnamoyloxy- 12-en-28-oic-acid (2), 2α,3β,19α-trihydroxy-urs-12-en-28-oic-acid (3), and ursolic acid (4), four known lignans, pinoresinol (5), 9α-hydroxypinoresinol (6), (+)-medioresinol (7), and (+)-kobusin (8), and two steroids, β-sitosterol (9), and daucosterol (10), were isolated from the whole parts of Teucrium viscidum. Their structures were established by a combination of spectroscopic data analysis, besides comparison with literature data. Compounds 1-4 were evaluated for their inhibitory activities against 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1). [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
9. Pentacyclic Triterpenes from Cecropia telenitida Can Function as Inhibitors of 11β-Hydroxysteroid Dehydrogenase Type 1
- Author
-
Aram J. Panay, Catalina Mosquera, and Guillermo Montoya
- Subjects
pentacyclic triterpene ,Cecropia ,Pharmaceutical Science ,PT ,Dehydrogenase ,BDS ,01 natural sciences ,Analytical Chemistry ,lcsh:QD241-441 ,chemistry.chemical_compound ,lcsh:Organic chemistry ,Triterpene ,11β-hydroxysteroid dehydrogenase type 1 ,CBX ,Drug Discovery ,Physical and Theoretical Chemistry ,11β-HSD1 ,11-β hydroxysteroid dehydrogenase type 1 ,chemistry.chemical_classification ,Natural product ,biology ,010405 organic chemistry ,Organic Chemistry ,biology.organism_classification ,Enzyme assay ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Enzyme ,chemistry ,Biochemistry ,Chemistry (miscellaneous) ,homogeneous time resolved fluorescence ,botanical dietary supplement ,biology.protein ,carbenoxolone ,Molecular Medicine ,Pentacyclic Triterpenes ,HTRF - Abstract
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 11&beta, 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 11&beta, 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 11&beta, hydroxysteroid dehydrogenase type 1 enzyme. Furthermore, a molecule displaying IC50 of 0.95 ±, 0.09 µ, M 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 11&beta, 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.
- Published
- 2018
- Full Text
- View/download PDF
10. A New Triterpenoid from Teucrium viscidum
- Author
-
Jinwen Zhang, Yanyan Si, Guangmin Yao, Zengwei Luo, Xincai Hao, Yonghui Zhang, Guangxin Xia, and Yongbo Xue
- Subjects
Liquid-Liquid Extraction ,Pharmaceutical Science ,Dehydrogenase ,Article ,Teucrium ,Analytical Chemistry ,lcsh:QD241-441 ,Structure-Activity Relationship ,Teucrium viscidum ,chemistry.chemical_compound ,Triterpenoid ,lcsh:Organic chemistry ,Ursolic acid ,Microsomes ,Drug Discovery ,Humans ,Enzyme Inhibitors ,Physical and Theoretical Chemistry ,11β-HSD1 ,Molecular Structure ,Traditional medicine ,Chemistry ,Organic Chemistry ,lignans ,triterpenoids ,Daucosterol ,Triterpenes ,HEK293 Cells ,Pinoresinol ,Chemistry (miscellaneous) ,Molecular Medicine ,11-beta-Hydroxysteroid Dehydrogenases ,Drugs, Chinese Herbal - Abstract
A new ursane-type triterpenoid, 3β-hydroxy-urs-30-p-Z-hydroxycinnamoyloxy-12-en-28-oic-acid (1), together with three known triterpenoids, 3β-hydroxy-urs-30-p-E-hydroxycinnamoyloxy-12-en-28-oic-acid (2), 2α,3β,19α-trihydroxy-urs-12-en-28-oic-acid (3), and ursolic acid (4), four known lignans, pinoresinol (5), 9α-hydroxypinoresinol (6), (+)-medioresinol (7), and (+)-kobusin (8), and two steroids, β-sitosterol (9), and daucosterol (10), were isolated from the whole parts of Teucrium viscidum. Their structures were established by a combination of spectroscopic data analysis, besides comparison with literature data. Compounds 1–4 were evaluated for their inhibitory activities against 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1).
- Published
- 2013
11. Pentacyclic Triterpenes from Cecropia telenitida Can Function as Inhibitors of 11β-Hydroxysteroid Dehydrogenase Type 1.
- Author
-
Mosquera, Catalina, Panay, Aram J., and Montoya, Guillermo
- Subjects
- *
TRITERPENES , *CECROPIA , *HYDROXYSTEROID dehydrogenases , *PLANT extracts , *HYPOGLYCEMIA - Abstract
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 ofCecropia 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 11β-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 ofCecropia telenitida molecules on 11β-hydroxysteroid dehydrogenase type 1 enzyme activity. A pre-fractionated chemical library was obtained from the roots ofCecropia 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 fromCecropia telenitida roots identified one fraction displaying 82% inhibition of the formation of cortisol by the 11β-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 fromCecropia telenitida can inhibit 11β-hydroxysteroid dehydrogenase type 1 enzyme activity. These findings highlight the potential ethnopharmacological use of plants from the genusCecropia for the treatment of metabolic disorders and diabetes. [ABSTRACT FROM AUTHOR]- Published
- 2018
- Full Text
- View/download PDF
12. Molecular Modeling Studies of 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors through Receptor-Based 3D-QSAR and Molecular Dynamics Simulations
- Author
-
Jiongjiong Chen, You-Lu Pan, Hai-Yan Qian, and Jian-Zhong Chen
- Subjects
0301 basic medicine ,Quantitative structure–activity relationship ,Molecular model ,Stereochemistry ,MESP ,Pharmaceutical Science ,01 natural sciences ,Article ,Analytical Chemistry ,lcsh:QD241-441 ,03 medical and health sciences ,Molecular dynamics ,lcsh:Organic chemistry ,Computational chemistry ,0103 physical sciences ,Drug Discovery ,11β-HSD1 ,3D-QSAR ,MD simulations ,binding free energy ,Physical and Theoretical Chemistry ,Mulliken population analysis ,010304 chemical physics ,Hydrogen bond ,Chemistry ,Organic Chemistry ,Rational design ,030104 developmental biology ,Chemistry (miscellaneous) ,Docking (molecular) ,Molecular Medicine ,Density functional theory - Abstract
11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is a potential target for the treatment of numerous human disorders, such as diabetes, obesity, and metabolic syndrome. In this work, molecular modeling studies combining molecular docking, 3D-QSAR, MESP, MD simulations and free energy calculations were performed on pyridine amides and 1,2,4-triazolopyridines as 11β-HSD1 inhibitors to explore structure-activity relationships and structural requirement for the inhibitory activity. 3D-QSAR models, including CoMFA and CoMSIA, were developed from the conformations obtained by docking strategy. The derived pharmacophoric features were further supported by MESP and Mulliken charge analyses using density functional theory. In addition, MD simulations and free energy calculations were employed to determine the detailed binding process and to compare the binding modes of inhibitors with different bioactivities. The binding free energies calculated by MM/PBSA showed a good correlation with the experimental biological activities. Free energy analyses and per-residue energy decomposition indicated the van der Waals interaction would be the major driving force for the interactions between an inhibitor and 11β-HSD1. These unified results may provide that hydrogen bond interactions with Ser170 and Tyr183 are favorable for enhancing activity. Thr124, Ser170, Tyr177, Tyr183, Val227, and Val231 are the key amino acid residues in the binding pocket. The obtained results are expected to be valuable for the rational design of novel potent 11β-HSD1 inhibitors.
- Published
- 2016
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