Abstract: One aspect of the present invention relates to methods of identifying cortisone response signature gene sets and methods of using the identified gene sets to identify compounds that modulate HSD1 activity. In some embodiments, methods are provided to use cortisone response gene sets to estimate the HSD1 activity. Another aspect of the present inventive relates to methods for identification of off-target signature gene sets that can be used to estimate HSD1 compound induced off-target activity and methods for classification of compounds that modulate HSD1 activity. Another aspect of the present invention relates to cell lines that over-expresses HSD1 and methods of use thereof. Additional embodiments of the of the invention are described in the specification provided herein. The contents of this ABSTRACT are not intended to in anyway limit the scope of the invention claimed herein.

Abstract: The present invention provides a method for the treatment or prevention of conditions which can be ameliorated by Smo antagonism, which method comprises administration to a patient in need thereof of an effective amount of a compound of formula I or a composition comprising a compound of formula I: or a pharmaceutically acceptable salt or solvate thereof; wherein: 2 of X, Y and Z represent nitrogen atoms, and the other represents an oxygen atom; R1 and R2 are taken together with the atom to which they are attached and represent a cyclobutyl ring, optionally substituted with 1-2 fluorine atoms, and R3 represents hydrogen or a fluorine atom; or R1 represents methyl, R2 represents methyl or a fluorine atom and R3 represents a fluorine atom.

Abstract: The present invention provides a method for the treatment or prevention of conditions which can be ameliorated by Smo antagonism, which method comprises administration to a patient in need thereof of an effective amount of a compound of formula I or a composition comprising a compound of formula I: or a pharmaceutically acceptable salt or solvate thereof; wherein: 2 of X, Y and Z represent nitrogen atoms, and the other represents an oxygen atom; R1 and R2 are taken together with the atom to which they are attached and represent a cyclobutyl ring, optionally substituted with 1-2 fluorine atoms, and R3 represents hydrogen or a fluorine atom; or R1 represents methyl, R2 represents methyl or a fluorine atom and R3 represents a fluorine atom.

Abstract: Compounds having Formula (I), including pharmaceutically acceptable salts and prodrugs thereof: are selective inhibitors of the 11?-HSD1 enzyme. They inhibit the 11?-HSD1-mediated conversion of cortisone and other 11-keto-glucocorticoids to cortisol and other 11?-hydroxy-glucocorticoids. The 11?-HSD1 inhibitors therefore decrease the amount of cortisol in target tissues, thereby modulating the effects of cortisol.

Abstract: Compounds having Formula (I), including pharmaceutically acceptable salts and prodrugs thereof: are selective inhibitors of the 11?-HSD1 enzyme. They inhibit the 11?-HSD1-mediated conversion of cortisone and other 11-keto-glucocorticoids to cortisol and other 11?-hydroxy-glucocorticoids. The 11?-HSD1 inhibitors therefore decrease the amount of cortisol in target tissues, thereby modulating the effects of cortisol. Modulation of cortisol may be effective in controlling non-insulin-dependent diabetes (NIDDM), hyperglycemia, obesity, insulin resistance, dyslipidemia, hyperlipidemia, hypertension, Syndrome X, and other symptoms associated with NIDDM or with excess cortisol in the body.