Limits...
Structure-based drug design targeting the cell membrane receptor GPBAR1: exploiting the bile acid scaffold towards selective agonism.

Di Leva FS, Festa C, Renga B, Sepe V, Novellino E, Fiorucci S, Zampella A, Limongelli V - Sci Rep (2015)

Bottom Line: A number of dual GPBAR1/FXR agonists are known, however their therapeutic use is limited by multiple unwanted effects due to activation of the diverse downstream signals controlled by the two receptors.On the other hand, designing selective GPBAR1 and FXR agonists is challenging since the two proteins share similar structural requisites for ligand binding.The presence of the 3α-NH2 group on the steroidal scaffold is responsible for the selectivity over FXR unveiling unprecedented structural insights into bile acid receptors activity modulation.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy, University of Naples "Federico II", Via D. Montesano 49, I-80131 Naples, Italy.

ABSTRACT
Bile acids can regulate nutrient metabolism through the activation of the cell membrane receptor GPBAR1 and the nuclear receptor FXR. Developing an exogenous control over these receptors represents an attractive strategy for the treatment of enterohepatic and metabolic disorders. A number of dual GPBAR1/FXR agonists are known, however their therapeutic use is limited by multiple unwanted effects due to activation of the diverse downstream signals controlled by the two receptors. On the other hand, designing selective GPBAR1 and FXR agonists is challenging since the two proteins share similar structural requisites for ligand binding. Here, taking advantage of our knowledge of the two targets, we have identified through a rational drug design study a series of amine lithocholic acid derivatives as selective GPBAR1 agonists. The presence of the 3α-NH2 group on the steroidal scaffold is responsible for the selectivity over FXR unveiling unprecedented structural insights into bile acid receptors activity modulation.

No MeSH data available.


Related in: MedlinePlus

Preparation of α-amino LCA derivatives.Reagents and conditions: a) p-TsCl, pyridine, quantitative; b) CH3COOK, DMF; H2O 5:1, reflux, 81%; c) MsCl, TEA; ethyl ether, 67%; d) NaN3, DMSO, DMF, 150 °C, 67%; e) H2 (1 atm), Pd/C, THF/MeOH 1:1, 44%; f) LiBH4, MeOH dry, THF, 0 °C, 54%; g) NaOH 5% in MeOH/H2O 1:1 v/v, 42%.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4645117&req=5

f5: Preparation of α-amino LCA derivatives.Reagents and conditions: a) p-TsCl, pyridine, quantitative; b) CH3COOK, DMF; H2O 5:1, reflux, 81%; c) MsCl, TEA; ethyl ether, 67%; d) NaN3, DMSO, DMF, 150 °C, 67%; e) H2 (1 atm), Pd/C, THF/MeOH 1:1, 44%; f) LiBH4, MeOH dry, THF, 0 °C, 54%; g) NaOH 5% in MeOH/H2O 1:1 v/v, 42%.

Mentions: Mesylation on LCA methyl ester 9 and subsequent treatment with NaN3 furnished the intermediate 3β-azido 11 (Fig. 4). Hydrogenation (H2, Pd/C) afforded methyl 3β-amino LCA 7 that was used as starting material for the preparation of 6 and 8 by methyl ester hydrolysis and methyl ester reduction, respectively (Fig. 4). The counterpart 3α-amino LCA derivatives were prepared following the synthetic protocol depicted in Fig. 5. Tosylation at C-3 hydroxyl group on LCA methyl ester followed by inversion of configuration with potassium acetate in DMF/H2O afforded the 3β-hydroxy derivative 12 in 81% over two steps, which was in turn transformed in the corresponding 3α-azido derivative 14 following the same synthetic protocol reported in Fig. 4. Hydrogenation at the azido group and elaboration of the functional group on the side chain afforded derivatives 3–5 in good chemical yield.


Structure-based drug design targeting the cell membrane receptor GPBAR1: exploiting the bile acid scaffold towards selective agonism.

Di Leva FS, Festa C, Renga B, Sepe V, Novellino E, Fiorucci S, Zampella A, Limongelli V - Sci Rep (2015)

Preparation of α-amino LCA derivatives.Reagents and conditions: a) p-TsCl, pyridine, quantitative; b) CH3COOK, DMF; H2O 5:1, reflux, 81%; c) MsCl, TEA; ethyl ether, 67%; d) NaN3, DMSO, DMF, 150 °C, 67%; e) H2 (1 atm), Pd/C, THF/MeOH 1:1, 44%; f) LiBH4, MeOH dry, THF, 0 °C, 54%; g) NaOH 5% in MeOH/H2O 1:1 v/v, 42%.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4645117&req=5

f5: Preparation of α-amino LCA derivatives.Reagents and conditions: a) p-TsCl, pyridine, quantitative; b) CH3COOK, DMF; H2O 5:1, reflux, 81%; c) MsCl, TEA; ethyl ether, 67%; d) NaN3, DMSO, DMF, 150 °C, 67%; e) H2 (1 atm), Pd/C, THF/MeOH 1:1, 44%; f) LiBH4, MeOH dry, THF, 0 °C, 54%; g) NaOH 5% in MeOH/H2O 1:1 v/v, 42%.
Mentions: Mesylation on LCA methyl ester 9 and subsequent treatment with NaN3 furnished the intermediate 3β-azido 11 (Fig. 4). Hydrogenation (H2, Pd/C) afforded methyl 3β-amino LCA 7 that was used as starting material for the preparation of 6 and 8 by methyl ester hydrolysis and methyl ester reduction, respectively (Fig. 4). The counterpart 3α-amino LCA derivatives were prepared following the synthetic protocol depicted in Fig. 5. Tosylation at C-3 hydroxyl group on LCA methyl ester followed by inversion of configuration with potassium acetate in DMF/H2O afforded the 3β-hydroxy derivative 12 in 81% over two steps, which was in turn transformed in the corresponding 3α-azido derivative 14 following the same synthetic protocol reported in Fig. 4. Hydrogenation at the azido group and elaboration of the functional group on the side chain afforded derivatives 3–5 in good chemical yield.

Bottom Line: A number of dual GPBAR1/FXR agonists are known, however their therapeutic use is limited by multiple unwanted effects due to activation of the diverse downstream signals controlled by the two receptors.On the other hand, designing selective GPBAR1 and FXR agonists is challenging since the two proteins share similar structural requisites for ligand binding.The presence of the 3α-NH2 group on the steroidal scaffold is responsible for the selectivity over FXR unveiling unprecedented structural insights into bile acid receptors activity modulation.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy, University of Naples "Federico II", Via D. Montesano 49, I-80131 Naples, Italy.

ABSTRACT
Bile acids can regulate nutrient metabolism through the activation of the cell membrane receptor GPBAR1 and the nuclear receptor FXR. Developing an exogenous control over these receptors represents an attractive strategy for the treatment of enterohepatic and metabolic disorders. A number of dual GPBAR1/FXR agonists are known, however their therapeutic use is limited by multiple unwanted effects due to activation of the diverse downstream signals controlled by the two receptors. On the other hand, designing selective GPBAR1 and FXR agonists is challenging since the two proteins share similar structural requisites for ligand binding. Here, taking advantage of our knowledge of the two targets, we have identified through a rational drug design study a series of amine lithocholic acid derivatives as selective GPBAR1 agonists. The presence of the 3α-NH2 group on the steroidal scaffold is responsible for the selectivity over FXR unveiling unprecedented structural insights into bile acid receptors activity modulation.

No MeSH data available.


Related in: MedlinePlus