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 Original Research Article

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-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 5αR1 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 appropriate for 5αR inhibition than the 5-phenyl-1-methyl-2-pyridones (I). Especially the 4′-carbonyl compounds 5–10 represent new lead structures for the development of novel human type 2 inhibitors.