Inhibition requirements of the human apical sodium-dependent bile acid transporter (hASBT) using aminopiperidine conjugates of glutamyl-bile acids.

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 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

SUBMITTER: Gonzalez PM 

PROVIDER: S-EPMC2882941 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature