Synthesis of N-substituted piperidine-4-(benzylidene-4-carboxylic acids) and evaluation as inhibitors of steroid-5alpha-reductase type 1 and 2 |
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Authors: | Picard F Baston E Reichert W Hartmann R W |
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Institution: | FR 12.1 Pharmazeutische und Medizinische Chemie, Universit?t des Saarlandes, Saarbrücken, Germany. |
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Abstract: | 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-propylpentanoyl (8), diphenylcarbamoyl (9), trimethylacetyl (10), 3,3-dimethylacryloyl (11), dicyclohexylacetyl derivative of the benzyl compound (12)]. Compounds were tested for inhibitory activity toward 5alpha-reductase isozymes 1 and 2 in human and rat. The test compounds inhibited 5alpha-reductase, showing a broad range of inhibitory potencies. In rat, compounds 6 (IC50 = 3.44 and 0.37 microM for type 1 and 2, respectively) and 9 (IC50=0.54 and 0.69 microM for type 1 and 2, respectively) displayed the best inhibition toward 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 type 1 enzyme (IC50 approximately 10 microM for rat and human enzyme). In vivo, selected compounds reduced prostate weights in castrated testosterone treated rats. |
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