243982-41-4Relevant articles and documents
Practical and scalable synthesis of orthogonally protected-2-substituted chiral piperazines
Chamakuri, Srinivas,Santini, Conrad,Shah, Manuj M.,Yang, David C. H.,Young, Damian W.
, p. 8844 - 8849 (2020/11/23)
A synthetic route to orthogonally protected, enantiomerically pure 2-substituted piperazines is described. Starting from α-amino acids, within four steps chiral 2-substituted piperazines are obtained. The key transformation involves an aza-Michael additio
Secondary amides of (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid as inhibitors of pyruvate dehydrogenase kinase
Aicher, Thomas D.,Anderson, Robert C.,Gao, Jiaping,Shetty, Suraj S.,Coppola, Gary M.,Stanton, James L.,Knorr, Douglas C.,Sperbeck, Donald M.,Brand, Leonard J.,Vinluan, Christine C.,Kaplan, Emma L.,Dragland, Carol J.,Tomaselli, Hollis C.,Islam, Amin,Lozito, Robert J.,Liu, Xilin,Maniara, Wieslawa M.,Fillers, William S.,Dominick Delgrande,Walter, Eric,Mann, William R.
, p. 236 - 249 (2007/10/03)
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.
