| Autor: |
Aicher, T. D., Anderson, R. C., Gao, J., Shetty, S. S., Coppola, G. M., Stanton, J. L., Knorr, D. C., Sperbeck, D. M., Brand, L. J., Vinluan, C. C., Kaplan, E. L., Dragland, C. J., Tomaselli, H. C., Islam, A., Lozito, R. J., Liu, X., Maniara, W. M., Fillers, W. S., DelGrande, D., Walter, R. E., Mann, W. R. |
| Zdroj: |
Journal of Medicinal Chemistry; January 27, 2000, Vol. 43 Issue: 2 p236-249, 14p |
| Abstrakt: |
N-Methyl-N-(4-tert-butyl-1,2,5,6-tetrahydropyridine)thiourea, SDZ048-619 (1), is a modest inhibitor (IC50 = 180 μM) of pyruvate dehydrogenase kinase (PDHK). In an optimization of the N-methylcarbothioamide moiety of 1, it was discovered that amides with a small acyl group, in particular appropriately substituted amides of (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid, are inhibitors of PDHK. Utilizing this acyl moiety, herein is reported the rationale leading to the optimization of a series of acylated piperazine derivatives. Methyl substitution of the piperazine at the 2- and 5-positions (with S and R absolute stereochemistry) markedly increased the potency of the lead compound (>1000-fold). Oral bioavailability of the compounds in this series is good and is optimal (as measured by AUC) when the 4-position of the piperazine is substituted with an electron-poor benzoyl moiety. (+)-1-N-[2,5-(S,R)-Dimethyl-4-N-(4-cyanobenzoyl)piperazine]-(R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (14e) inhibits PDHK in the primary enzymatic assay with an IC50 of 16 ± 2 nM, enhances the oxidation of [14C]lactate into 14CO2 in human fibroblasts with an EC50 of 57 ± 13 nM, diminishes lactate significantly 2.5 h post-oral-dose at doses as low as 1 μmol/kg, and increases the ex vivo activity of PDH in muscle, liver, and fat tissues in normal Sprague−Dawley rats. These PDHK inhibitors, however, do not lower glucose in diabetic animal models. |
| Databáze: |
Supplemental Index |
| Externí odkaz: |
|
