Synthesis of N-substituted piperidine-4-(benzylidene-4-carboxylic acids) and evaluation as inhibitors of steroid-5 alpha-reductase type 1 and 2

The synthesis of N-substituted piperidine-4-(benzylidene-4-carboxylic acids ) is described [benzoyl (1), benzyl (2), adamantanoyl (3), cyclohexanoyl (4 ), cyclohexylacetyl (5), diphenylacetyl (6), dicyclohexylacetyl (7), 2-prop ylpentanoyl (8), diphenylcarbamoyl (9). trimethylacetyl (10), 3,3-dimethyla cryloyl (11), dicyclohexylacetyl derivative of the benzyl compound (12)]. C ompounds were tested for inhibitory activity toward Scc-reductase isozymes 1 and 2 in human and rat. The test compounds inhibited 5 alpha-reductase, s howing a broad range of inhibitory potencies. In rat, compounds 6 (IC50 = 3 .44 and 0.37 mu M for type 1 and 2, respectively) and 9 (IC50 = 0.54 and 0. 69 mu M for type 1 and 2, respectively) displayed the best inhibition towar d both Isozymes. Compound 7 showed a strong inhibition toward type 2 human and rat enzyme (IC50 = 60 and 80 nM) but only a moderate activity versus ty pe 1 enzyme (IC50 approximately 10 mu M for rat and human enzyme). In vivo, selected compounds reduced prostate weights in castrated testosterone trea ted rats. (C) 2000 Elsevier Science Ltd. All rights reserved.