19-NOR-10-AZASTEROIDS, A NEW CLASS OF STEROID 5-ALPHA-REDUCTASE INHIBITORS .2. X-RAY STRUCTURE, MOLECULAR MODELING, CONFORMATIONAL-ANALYSISOF 19-NOR-10-AZASTEROIDS AND COMPARISON WITH 4-AZASTEROIDS AND 6-AZASTEROIDS

19-Nor-10-azasteroids are a new class of 5 alpha-reductase inhibitors whose activity depends on the presence of the bridgehead N-10 atom con jugated with the 4-en-3-one moiety in the A ring. The X-ray structure of 19-nor-10-azasteroid 1 has been determined and it is compared with the X-ray structure of testosterone. A complete conformational analysi s of these compounds has been performed, determining the number and en ergy of the possible conformers, as well as the molecular flexibility of the 10-azasteroidal skeleton. Thus, MM2: molecular mechanics calcu lations and AM1 semiempirical energy refinements revealed that 19-nor- 10-azasteroids 1-3 have four possible conformations with very small en ergy differences and that they are very flexible molecules. The confor mational analysis has been extended to testosterone (4), which also sh owed conformational flexibility, with three different conformations, a nd to 6-azasteroid 5 and 4-azasteroid 6, for which only two thermally accessible conformations have been found. Compared to 19-nor-10-azaste roids 1-3, azasteroids 5 and 6 appear to be more rigid structures. By a best fit analysis of all conformers of 1-5 with the global minimum o f testosterone (4-I) it has been found that the lowest energy conforme rs of 1, 3, and 5 are very close to the structure of 4-I, and among th e conformers of 2, the best similarity has been observed for the highe st energy conformer 2-IV.