Inhibition requirements of the human apical sodium-dependent bile acid transporter (hASBT) using aminopiperidine conjugates of glutamyl-bile acids.
OBJECTIVE
Synthesize aminopiperidine conjugates of glutamyl-bile acids (glu-BAs) and develop a hASBT inhibition model using the conformationally sampled pharmacophore (CSP) approach.


METHODS
glu-BAs aminopiperidine conjugates were synthesized. hASBT inhibition was measured as K(i). A CSP-SAR model was built using structural and physico-chemical descriptors and evaluated via cross-validation.


RESULTS
Twenty-nine aminopiperidine conjugates were synthesized. All inhibited hASBT, with K(i) ranging from 0.95 to 31.8 muM. Amidation of the piperidine nitrogen slightly decreased activity, while replacement by a carbon increased potency. Esterification of the glutamic acid linker had a minor impact, suggesting that a negative charge around C-24 is not required for binding. Three quantitative CSP-SAR models were developed. The best model (r (2) = 0.813, Q (2) = 0.726) included two descriptors: angle between 7-OH, alpha-substituent and centroid of rings B and C, and electrostatic contribution to the solvation free-energy. The model successfully distinguished between compounds with K(i) < 16muM and K(i) > 16muM. Models indicated that hydrophobicity, alpha substituent orientation, and partially compacted side chain conformation promote inhibitory potency. Qualitative CSP-SAR analysis indicated that the presence of an internal salt bridge, resulting in a locked conformation of the side chain, yielded weaker inhibitors.


CONCLUSIONS
Aminopiperidine conjugates of glu-BAs were potent hASBT inhibitors. A predictive and robust CSP-SAR model was developed.
González
Pablo M
PM
Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, 20 Penn Street, HSF2 room 623, Baltimore, Maryland 21201, USA.
Acharya
Chayan
C
Mackerell
Alexander D
AD
Polli
James E
JE
D000818:Animals; D001647:Bile Acids and Salts / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D002460:Cell Line; D003198:Computer Simulation; D004285:Dogs; D018698:Glutamic Acid / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D029363:Organic Anion Transporters, Sodium-Dependent / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D027981:Symporters / Q000037:antagonists & inhibitors* / Q000378:metabolism*
C481395:4-aminopiperidine; D001647:Bile Acids and Salts; D029363:Organic Anion Transporters, Sodium-Dependent; D010880:Piperidines; D027981:Symporters; C071908:sodium-bile acid cotransporter; D018698:Glutamic Acid