Advances in the stereoselective synthesis of antifungal agents and ...

Chapter 1 2715 is an advanced representative of the new class of azoheterocyclicinhibitors of aromatase currently under clinical evaluation 131 .NNCNH15Figure 1.16: (S)-(-) Fadrozole 15.The pharmacological evaluation of Fadrozole hydrocloride 15 provesthis drug to be a very potent inhibitor which effectively inhibits aromatase invivo with an ED 50 = 0.03 mg/kg 132 leading to a significant reduction ofestrogen levels. The excellent selectivity for aromatase over desmolasesupports the working hypothesis that the strong binding to iron isresponsible for the higher potency of the imidazoles and that thecomplementarity of the inhibitor with the steroid binding site - whileenhancing this potency- more importantly provides selectivity for aromataseover desmolase and other cytochrome P-450 enzymes 133 .Fadrozole 15 has a chiral centre in the benzylic position; the twoenantiomers have been separated by chiral HPLC and the absoluteconfiguration has been assigned by X-ray analysis of its corresponding saltwith D-(-)-tartaric acid 134 . The S - configuration was assigned to the (-)-enantiomer that was shown to be responsible for the high aromataseinhibitory activity of fadrozole 134 .The cyano function in the para position of the phenyl ring it is anessential structural requirement for the high inhibitory activity in fadrozoleand its analogues 133 . In fact it seems possible that this polar group mightmimic one of the carbonyl functions of the steroidal inhibitors, either that ofthe A or that of the D ring 134 .Ciba Geigy further developed the 1,2,4 - triazole derivatives CGS20267 16 135 , the most potent aromatase inhibitor in vivo reported by theend of 1993 (Fig. 1.17).