243982-46-9Relevant academic research and scientific papers
Benzenesulfonamide-derivatives and their use as medicaments
-
Page column 72, (2010/11/30)
Compounds of formula (I), pharmaceutically acceptable salts or in vivo hydrolysable esters thereof, wherein: Ring X is phenyl or a six membered heteroaryl ring containing one or two ring nitrogens where said nitrogens are optionally oxidised to form the N
Use of compounds for the elevation of pyruvate dehydrogenase activity
-
, (2008/06/13)
The use of compounds of the formula (I), and salts thereof; and pharmaceutically acceptable in vivo cleavable prodrugs of said compound of formula (I); and pharmaceutically acceptable salts of said compound or said prodrugs: wherein: Ring C is phenyl or a carbon linked heteroaryl ring substituted as defmed within; R1is an ortho substituent as defined within; n is 1 or 2; A—B is a linking group as defined within; R2and R3are as defined within; R4is hydroxy, hydrogen, halo, amino or methyl; in the manufacture of a medicament for use in the elevation of PDH activity in warm-blooded animals such as humans is described. Pharmaceutical compositions, methods and processes for preparation of compounds of formula (I) are also described.
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.
