PREPARATIVE CHIRAL HPLC SEPARATION OF ALL POSSIBLE STEREOISOMERS OF LY191704 AND LY266111 AND THEIR IN-VITRO INHIBITION OF HUMAN TYPE-1 ANDTYPE-2 STEROID 5-ALPHA-REDUCTASES

A preparative chiral HPLC separation of each of the four stereoisomers of LY191704 [(+/-)-1, and (+/-)-3] and LY266111 [(+/-)-2, and (+/-)4] is reported. All eight compounds have been evaluated in vitro as inhi bitors of recombinant human type 1 and type 2 steroid 5alpha-reductase . The trans enantiomers of LY266111, (+)-2 and (-)-2, show equal and p otent inhibition of the type 1 isozyme. The cis enantiomers of LY26611 1, (+)-4 and (-)-4, and the unsaturated analogue 6 show significantly reduced type 1 inhibitory activity. The cis and trans enantiomeric pai rs of LY191704 [(+)-1, (-)-1, (+)-3, and (-)-3] and the unsaturated an alog 5 display similar and potent activity against the type 1 isozyme. All compounds display relatively poor activity against the human type 2 isozyme.