954232-31-6Relevant academic research and scientific papers
Development of a series of aryl pyrimidine kynurenine monooxygenase inhibitors as potential therapeutic agents for the treatment of Huntingtons disease
Toledo-Sherman, Leticia M.,Prime, Michael E.,Mrzljak, Ladislav,Beconi, Maria G.,Beresford, Alan,Brookfield, Frederick A.,Brown, Christopher J.,Cardaun, Isabell,Courtney, Stephen M.,Dijkman, Ulrike,Hamelin-Flegg, Estelle,Johnson, Peter D.,Kempf, Valerie,Lyons, Kathy,Matthews, Kimberly,Mitchell, William L.,Oconnell, Catherine,Pena, Paula,Powell, Kendall,Rassoulpour, Arash,Reed, Laura,Reindl, Wolfgang,Selvaratnam, Suganathan,Friley, Weslyn Ward,Weddell, Derek A.,Went, Naomi E.,Wheelan, Patricia,Winkler, Christin,Winkler, Dirk,Wityak, John,Yarnold, Christopher J.,Yates, Dawn,Munoz-Sanjuan, Ignacio,Dominguez, Celia
, p. 1159 - 1183 (2015/03/04)
We report on the development of a series of pyrimidine carboxylic acids that are potent and selective inhibitors of kynurenine monooxygenase and competitive for kynurenine. We describe the SAR for this novel series and report on their inhibition of KMO activity in biochemical and cellular assays and their selectivity against other kynurenine pathway enzymes. We describe the optimization process that led to the identification of a program lead compound with a suitable ADME/PK profile for therapeutic development. We demonstrate that systemic inhibition of KMO in vivo with this lead compound provides pharmacodynamic evidence for modulation of kynurenine pathway metabolites both in the periphery and in the central nervous system.
(3R,4S)-4-(2,4,5-Trifluorophenyl)-pyrrolidin-3-ylamine inhibitors of dipeptidyl peptidase IV: Synthesis, in vitro, in vivo, and X-ray crystallographic characterization
Wright, Stephen W.,Ammirati, Mark J.,Andrews, Kim M.,Brodeur, Anne M.,Danley, Dennis E.,Doran, Shawn D.,Lillquist, Jay S.,Liu, Shenping,McClure, Lester D.,McPherson, R. Kirk,Olson, Thanh V.,Orena, Stephen J.,Parker, Janice C.,Rocke, Benjamin N.,Soeller, Walter C.,Soglia, Carolyn B.,Treadway, Judith L.,VanVolkenburg, Maria A.,Zhao, Zhengrong,Cox, Eric D.
, p. 5638 - 5642 (2008/02/13)
A series of pyrrolidine based inhibitors of dipeptidyl peptidase IV were developed from a high throughput screening hit for the treatment of type 2 diabetes. Potency, selectivity, and pharmacokinetic properties were optimized resulting in the identification of a pre-clinical candidate for further profiling.
