327058-58-2Relevant articles and documents
5-Phenyl substituted 1-methyl-2-pyridones and 4′-substituted biphenyl-4-carboxylic acids. synthesis and evaluation as inhibitors of steroid-5α-reductase type 1 and 2
Picard, Franck,Schulz, Tobias,Hartmann, Rolf W.
, p. 437 - 448 (2007/10/03)
The synthesis of a series of 5-phenyl substituted 1-methyl-2-pyridones (I) and 4′-substituted biphenyl-4-carboxylic acids (II) as novel A-C ring steroidomimetic inhibitors of 5α-reductase (5αR) is described. Compounds 1-4 (I) were synthesized by palladium catalyzed cross coupling (Ishikura) reaction between diethyl(3-pyridyl)borane and aryl halides (1b-4b) followed by α-oxidation with sodium ferrocyanate of the 1-methyl-pyridinium salt. Inhibitors II (5-18) were obtained either by two successive Friedel-Crafts acylations from biphenyl (5a-10a) followed by saponification to yield the corresponding carboxylic acids (5-10) or by Suzuki cross coupling reaction to give the 4′-substituted biphenyl 1-4-carbaldehydes 11a-18a. The latter compounds were subjected to a Lindgren oxidation to yield compounds 11-18. The compounds were tested for inhibitory activity toward human and rat 5 αR1 and 2. The test compounds inhibited 5αR, showing a broad range of inhibitory potencies. The best compound in series I was the N-(dicyclohexyl)-4-(1,2-dihydro-1-methyl-2-oxopyrid-5-yl) benzamide 4 exhibiting an IC50 value for the human type 2 enzyme of 10 μM. In series II, the most active compound toward human type 2 isozyme was the 4′-(dicyclohexyl)acetyl-4-biphenyl carboxylic acid (10; IC50 = 220 nM). Both series showed only marginal activity toward the human type 1 isozyme. In conclusion, the biphenyl carboxylic acids (II) are more appropiate for 5αR inhibition than the 5-phenyl-1-methyl-2-pyridones (1). Especially the 4′-carbonyl compounds 5-10 represent new lead structures for the development of novel human type 2 inhibitors. Copyright
