54289-73-5Relevant academic research and scientific papers
Design, synthesis, and biological evaluation of potent and selective class IIa histone deacetylase (HDAC) inhibitors as a potential therapy for huntington's disease
Bürli, Roland W.,Luckhurst, Christopher A.,Aziz, Omar,Matthews, Kim L.,Yates, Dawn,Lyons, Kathy. A.,Beconi, Maria,McAllister, George,Breccia, Perla,Stott, Andrew J.,Penrose, Stephen D.,Wall, Michael,Lamers, Marieke,Leonard, Philip,Müller, Ilka,Richardson, Christine M.,Jarvis, Rebecca,Stones, Liz,Hughes, Samantha,Wishart, Grant,Haughan, Alan F.,O'Connell, Catherine,Mead, Tania,McNeil, Hannah,Vann, Julie,Mangette, John,Maillard, Michel,Beaumont, Vahri,Munoz-Sanjuan, Ignacio,Dominguez, Celia
supporting information, p. 9934 - 9954 (2014/01/17)
Inhibition of class IIa histone deacetylase (HDAC) enzymes have been suggested as a therapeutic strategy for a number of diseases, including Huntington's disease. Catalytic-site small molecule inhibitors of the class IIa HDAC4, -5, -7, and -9 were developed. These trisubstituted diarylcyclopropanehydroxamic acids were designed to exploit a lower pocket that is characteristic for the class IIa HDACs, not present in other HDAC classes. Selected inhibitors were cocrystallized with the catalytic domain of human HDAC4. We describe the first HDAC4 catalytic domain crystal structure in a "closed-loop" form, which in our view represents the biologically relevant conformation. We have demonstrated that these molecules can differentiate class IIa HDACs from class I and class IIb subtypes. They exhibited pharmacokinetic properties that should enable the assessment of their therapeutic benefit in both peripheral and CNS disorders. These selective inhibitors provide a means for evaluating potential efficacy in preclinical models in vivo.
Discovering novel chemical inhibitors of human cyclophilin A: Virtual screening, synthesis, and bioassay
Li, Jian,Chen, Jing,Gui, Chunshan,Zhang, Li,Qin, Yu,Xu, Qiang,Zhang, Jian,Liu, Hong,Shen, Xu,Jiang, Hualiang
, p. 2209 - 2224 (2007/10/03)
Cyclophilin A (CypA) is a member of cyclophilins, a family of the highly homologous peptidyl prolyl cis-trans isomerases (PPIases), which can bind to cyclosporin A (CsA). CypA plays critical roles in various biological processes, including protein folding, assembly, transportation, regulation of neuron growth, and HIV replication. The discovery of CypA inhibitor is now of a great special interest in the treatment of immunological disorders. In this study, a series of novel small molecular CypA inhibitors have been discovered by using structure-based virtual screening in conjunction with chemical synthesis and bioassay. The SPECS_1 database containing 85,000 small molecular compounds was searched by virtual screening against the crystal structure of human CypA. After SPR-based binding affinity assay, 15 compounds were found to show binding affinities to CypA at submicro-molar or micro-molar level (compounds 1-15). Seven compounds were selected as the starting point for the further structure modification in considering binding activity, synthesis difficulty, and structure similarity. We thus synthesized 40 new small molecular compounds (1-6, 15, 16a-q, 17a-d, and 18a-l), and four of which (compounds 16b, 16h, 16k, and 18g) showed high CypA PPIase inhibition activities with IC50s of 2.5-6.2 μM. Pharmacological assay indicated that these four compounds demonstrated somewhat inhibition activities against the proliferation of spleen cells.
