Abstract

Purpose: 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 Ki. 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 Ki ranging from 0.95 to 31.8 µM. 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, a-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?<?16µM and Ki?>?16µM. Models indicated that hydrophobicity, a 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. © 2009 Springer Science+Business Media, LLC.