Preparative chiral HPLC separation of all possible stereoisomers of LY191704 and LY266111 and their in vitro inhibition of human types 1 and 2 steroid 5α-reductases

Abstract

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 inhibitors of recombinant human type 1 and type 2 steroid 5α-reductase. The trans enantiomers of LY266111, (+)- 2 and (−)- 2, show equal and potent inhibition of the type 1 isozyme. The cis enantiomers of LY266111, (+)- 4 and (−)- 4, and the unsaturated analogue 6 show significantly reduced type 1 inhibitory activity. The cis and trans enantiomeric pairs of LY191704 [(+)- 1, (−)- 1, (+)- 3, and (−)- 3] and the unsaturated analog 5 display similar and potent activity against the type 1 isozyme. All compounds display relatively poor activity against the human type 2 isozyme.