| Abstract
| - To identify enantioselective nonsteroidal aromatase inhibitors, a multidisciplinary medicinalchemistry approach was pursued. First, our earlier CoMFA model [Bioorg. Med. Chem. 1998,6, 377−388] was extended taking purposely into account previously discovered enantioselectivearomatase inhibitors. The 3D QSAR model was then exploited to design chiral ligands, whoseconfigurational assignment was obtained, after HPLC separation, by means of a combinationof circular dichroism measurements and time dependent density functional calculations. Finally,the new enantiomeric inhibitors were separately tested to ascertain both their potency againstthe cytochrome P450 aromatase (CYP19; EC 1.14.14.1), and their selectivity relative to anotherenzyme of the P450 family. A satisfactory agreement between experimental and predicted dataallowed us to assert that a properly built “enantioselective CoMFA model” might constitute auseful tool for addressing enantioselective ligands design.
|
