Design and synthesis of non-steroidal inhibitors of 5α-reductase
Androgen-dependent prostate cancer (PC) and benign prostate hyperplasia (BPH) can be treated either by surgical resection or through the use of drugs that produce androgen deprivation. Inhibition of the enzyme 5[alpha]-reductase (5[alpha]R), which is a membrane-bound NADPH-dependent protein and which metabolises testosterone to dihydrotestosterone (DHT) within androgen-dependent target cells, has been under investigation as a possible chemotherapeutic target for the treatment of BPH, and possibly of PC, although the correlation between the two diseases has yet to be determined. Due to the localisation of this protein within the membrane, attempts to gain information regarding the active site of 5[alpha]R have been slow. As such, a molecular modeling study of both steroidal and non-steroidal inhibitors of 5[alpha]R was undertaken in order to elucidate the essential requirements needed for the design of novel non¬steroidal inhibitors. It suggests that: (i) there is a requirement for groups to mimic the carbonyl group at the C3-position of the steroid substrate A-ring; (ii) the area about the C3, C4, CS and C6-positions of testosterone appears to be sterically hindered, presumably due to the binding of the NADPH moiety; (iii) the area of the active site about the C17-0H position of the substrate does not appear to possess hydrogen bonding groups and is unrestricted. Using the modeling data, a number of steroidal and non-steroidal compounds based upon N- and 3-substituted pyrrolidine-2,S-diones has been designed and their synthesis attempted using a number of reaction schemes.