96938-90-8Relevant academic research and scientific papers
Dual Glycolate Oxidase/Lactate Dehydrogenase A Inhibitors for Primary Hyperoxaluria
Ding, Jinyue,Gumpena, Rajesh,Boily, Marc-Olivier,Caron, Alexandre,Chong, Oliver,Cox, Jennifer H.,Dumais, Valerie,Gaudreault, Samuel,Graff, Aaron H.,King, Andrew,Knight, John,Oballa, Renata,Surendradoss, Jayakumar,Tang, Tim,Wu, Joyce,Lowther, W. Todd,Powell, David A.
, p. 1116 - 1123 (2021)
Both glycolate oxidase (GO) and lactate dehydrogenase A (LDHA) influence the endogenous synthesis of oxalate and are clinically validated targets for treatment of primary hyperoxaluria (PH). We investigated whether dual inhibition of GO and LDHA may provide advantage over single agents in treating PH. Utilizing a structure-based drug design (SBDD) approach, we developed a series of novel, potent, dual GO/LDHA inhibitors. X-ray crystal structures of compound 15 bound to individual GO and LDHA proteins validated our SBDD strategy. Dual inhibitor 7 demonstrated an IC50 of 88 nM for oxalate reduction in an Agxt-knockdown mouse hepatocyte assay. Limited by poor liver exposure, this series of dual inhibitors failed to demonstrate significant PD modulation in an in vivo mouse model. This work highlights the challenges in optimizing in vivo liver exposures for diacid containing compounds and limited benefit seen with dual GO/LDHA inhibitors over single agents alone in an in vitro setting.
Transaminations of Enaminones: A Synthesis of Tricyclic, N-Aryl, 1,2,3-Triazole-fused Pyridones
Chan, Tze-Ming,Friary, R.,Jones, H.,Schwerdt, J. H.,Seidl, V.,et al.
, p. 1135 - 1142 (2007/10/02)
1-Phenylmethyl- and 1-(4-methoxyphenylmethyl)-5-chloro-1,2,3-triazole-4-carbonyl chlorides acylated the pyrrolidine enamines of cyclopentanone and cyclohexanone, and the resulting enaminones underwent transaminations with aryl amines under acidic conditions.The products then cyclized under basic conditions to linearly fused, tricyclic 3-phenylmethyl- and 3-(4-methoxyphenylmethyl)-4-aryl-8-oxo-4,5,6,7-tetrahydrocyclopenta-1,2,3-triazolopyridines, and to 5,6,7,8-tetrahydro-4-aryl-3H-1,2,3-triazoloquinolin-9(4H)-ones.Similar transaminations afforded the related 8-phenyl- and 8-(3-chlorophenyl)-1,5,7,8-tetrahydro-1-(phenylmethyl)-4H-thieno-1,2,3-triazolopyridin-4-ones.Phase-transfer and catalytic hydrogenolyses of some of these intermediates furnished 4-aryl-8-oxo-4,5,6,7-tetrahydrocyclopenta-1,2,3-triazolopyridines and 4-aryl-5,6,7,8-tetrahydro-3H-1,2,3-triazoloquinoline-9(4H)-ones.The 3-(4-methoxyphenylmethyl)-4-aryl intermediates were sterically crowded.Two protons from the methoxyphenylmethylphenylmethylgroups were dramatically shielded because of anisotropic effects exerted by the 4-aryl substituents.
Studies on 1,2,3-Triazoles. Part XI. A New Entry to the Benzopyrano-1,2,3-triazole System. Cyclization of 1-Benzyl-5-chloro-4-(2-hydroxybenzoyl)-1H-1,2,3-triazoles
Buckle, Derek R.
, p. 77 - 80 (2007/10/02)
The acylation of simple arenes such as benzene and alkylated benzenes with N-protected 5-chloro-1H-1,2,3-triazole-4-carboxylic acid chlorides under Friedel-Crafts conditions results in excellent yields of the corresponding ketones.Resorcinol dimethyl ethe
