232275-49-9Relevant articles and documents
Definitive Metabolite Identification Coupled with Automated Ligand Identification System (ALIS) Technology: A Novel Approach to Uncover Structure-Activity Relationships and Guide Drug Design in a Factor IXa Inhibitor Program
Zhang, Ting,Liu, Yong,Yang, Xianshu,Martin, Gary E.,Yao, Huifang,Shang, Jackie,Bugianesi, Randal M.,Ellsworth, Kenneth P.,Sonatore, Lisa M.,Nizner, Peter,Sherer, Edward C.,Hill, Susan E.,Knemeyer, Ian W.,Geissler, Wayne M.,Dandliker, Peter J.,Helmy, Roy,Wood, Harold B.
, p. 1818 - 1829 (2016)
A potent and selective Factor IXa (FIXa) inhibitor was subjected to a series of liver microsomal incubations, which generated a number of metabolites. Using automated ligand identification system-affinity selection (ALIS-AS) methodology, metabolites in the incubation mixture were prioritized by their binding affinities to the FIXa protein. Microgram quantities of the metabolites of interest were then isolated through microisolation analytical capabilities, and structurally characterized using MicroCryoProbe heteronuclear 2D NMR techniques. The isolated metabolites recovered from the NMR experiments were then submitted directly to an in vitro FIXa enzymatic assay. The order of the metabolites' binding affinity to the Factor IXa protein from the ALIS assay was completely consistent with the enzymatic assay results. This work showcases an innovative and efficient approach to uncover structure-activity relationships (SARs) and guide drug design via microisolation-structural characterization and ALIS capabilities.
Identification of an imidazopyridine scaffold to generate potent and selective TYK2 inhibitors that demonstrate activity in an in vivo psoriasis model
Liang, Jun,Van Abbema, Anne,Balazs, Mercedesz,Barrett, Kathy,Berezhkovsky, Leo,Blair, Wade S.,Chang, Christine,Delarosa, Donnie,DeVoss, Jason,Driscoll, Jim,Eigenbrot, Charles,Goodacre, Simon,Ghilardi, Nico,MacLeod, Calum,Johnson, Adam,Bir Kohli, Pawan,Lai, Yingjie,Lin, Zhonghua,Mantik, Priscilla,Menghrajani, Kapil,Nguyen, Hieu,Peng, Ivan,Sambrone, Amy,Shia, Steven,Smith, Jan,Sohn, Sue,Tsui, Vickie,Ultsch, Mark,Williams, Karen,Wu, Lawren C.,Yang, Wenqian,Zhang, Birong,Magnuson, Steven
supporting information, p. 4370 - 4376 (2017/09/12)
Herein we report identification of an imidazopyridine class of potent and selective TYK2 inhibitors, exemplified by prototype 6, through constraint of the rotatable amide bond connecting the pyridine and aryl rings of compound 1. Further optimization led to generation of compound 30 that potently inhibits the TYK2 enzyme and the IL-23 pathway in cells, exhibits selectivity against cellular JAK2 activity, and has good pharmacokinetic properties. In mice, compound 30 demonstrated dose-dependent reduction of IL-17 production in a PK/PD model as well as in an imiquimod-induced psoriasis model. In this efficacy model, the IL-17 decrease was accompanied by a reduction of ear thickness indicating the potential of TYK2 inhibition as a therapeutic approach for psoriasis patients.
Preparation of fluorous Yamaguchi reagents and evaluation of their reactivity in esterification
Nishio, Yuya,Kawazu, Akari,Hirano, Shun,Matsubara, Hiroshi
, p. 720 - 725 (2016/01/15)
Fluorous Yamaguchi (FY) reagents bearing a perfluoroalkyl chain were prepared and employed in esterification reactions; the yields were similar to those obtained with the traditional Yamaguchi (TY) reagent. Fluorous benzoic acids derived from the FY reagents were separated easily after the reaction. GC analysis revealed that the initial rates of reaction with the FY reagents were higher than those with the TY reagent. The acidities of benzoic acids produced from the FY and TY reagents were predicted by DFT to be similar (1.20 and 0.96, respectively).
