Chiral derivatives of 2-cyclohexylideneperhydro-4,7-methanoindenes, a novel class of nonsteroidal androgen receptor ligand: synthesis, X-ray analysis, and biological activity.

A series of 2-cyclohexylideneperhydro-4,7-methanoindene derivatives was synthesized as novel androgen receptor ligands. Asymmetric hydroboration of key intermediate 2 afforded single enantiomer alcohol derivatives (3aR)-3 and (3aS)-3 which could be further transformed to give 12 variously substituted keto alcohol target compounds. X-ray crystallography of the 4-bromobenzenesulfonyl ester (3aS)-13 was used to establish their absolute configuration. The binding of these compounds to the rat ventral prostate androgen receptor showed moderate affinity with IC(50) values of 1.2 microM and above but with substantial enantiomeric dependencies which varied in accordance to Pfieffer's rule. Surprisingly, the (3aS)-5alpha-alcohols displayed similar affinity to the (3aR)-5beta-alcohols, and molecular modeling suggested an alternative mode of binding for the (3aS) series. The three compounds with the best androgen receptor affinity were assayed in vivo for antiandrogenic and androgenic effects on sex accessory organ growth in castrated immature rats and were found to be ineffective.