The present invention provides compounds, pharmaceutical compositions and
methods that are useful in modulating the farnesoid X receptor (FXR). As
FXR is involved in negatively controlling the expression level of
cholesterol 7.alpha.-hydroxylase (cyp7a), the rate-limiting enzyme
involved in the oxidative metabolism of cholesterol into bile acids, the
compounds described herein find utility in treating diseases associated
with abnormally high or low cholesterol levels. In certain aspects, the
FXR modulators (e.g., antagonists) described herein block the negative
feed-back downregulation of cyp7a expression produced by certain cholic
acids, the endogenous ligands for FXR. Moreover, as FXR forms
heterodimers with the retinoid X receptor (RXR) in some cell types,
modulation of the level of FXR activity in cells has a wide range of
effects on a variety of biological processes which are mediated by RXR or
other RXR-interacting proteins such as PPAR.gamma. and PPAR.alpha.. Thus,
compounds described herein are useful in treating other biological
activities such as obesity, diabetes, lipid associated disorders, cancer,
inflammatory disorders, disorders involving a disrupted or dysfunctional
epidermal barrier, and various other metabolic disorders.