519059-08-6Relevant academic research and scientific papers
The impact of binding site waters on the activity/selectivity trade-off of Janus kinase 2 (JAK2) inhibitors
Egyed, Attila,Bajusz, Dávid,Keser?, Gy?rgy M.
, p. 1497 - 1508 (2019/03/05)
Structure based optimization of B39, an indazole-based low micromolar JAK2 virtual screening hit is reported. Analysing the effect of certain modifications on the activity and selectivity of the analogues suggested that these parameters are influenced by
Structural Basis for Achieving GSK-3β Inhibition with High Potency, Selectivity, and Brain Exposure for Positron Emission Tomography Imaging and Drug Discovery
Bernard-Gauthier, Vadim,Mossine, Andrew V.,Knight, Ashley,Patnaik, Debasis,Zhao, Wen-Ning,Cheng, Chialin,Krishnan, Hema S.,Xuan, Lucius L.,Chindavong, Peter S.,Reis, Surya A.,Chen, Jinshan Michael,Shao, Xia,Stauff, Jenelle,Arteaga, Janna,Sherman, Phillip,Salem, Nicolas,Bonsall, David,Amaral, Brenda,Varlow, Cassis,Wells, Lisa,Martarello, Laurent,Patel, Shil,Liang, Steven H.,Kurumbail, Ravi G.,Haggarty, Stephen J.,Scott, Peter J. H.,Vasdev, Neil
supporting information, p. 9600 - 9617 (2019/10/28)
Using structure-guided design, several cell based assays, and microdosed positron emission tomography (PET) imaging, we identified a series of highly potent, selective, and brain-penetrant oxazole-4-carboxamide-based inhibitors of glycogen synthase kinase-3 (GSK-3). An isotopologue of our first-generation lead, [3H]PF-367, demonstrates selective and specific target engagement in vitro, irrespective of the activation state. We discovered substantial ubiquitous GSK-3-specific radioligand binding in Tg2576 Alzheimer's disease (AD), suggesting application for these compounds in AD diagnosis and identified [11C]OCM-44 as our lead GSK-3 radiotracer, with optimized brain uptake by PET imaging in nonhuman primates. GSK-3β-isozyme selectivity was assessed to reveal OCM-51, the most potent (IC50 = 0.030 nM) and selective (>10-fold GSK-3β/GSK-3α) GSK-3β inhibitor known to date. Inhibition of CRMP2T514 and tau phosphorylation, as well as favorable therapeutic window against WNT/β-catenin signaling activation, was observed in cells.
Discovery of a selective S1P1 receptor agonist efficacious at low oral dose and devoid of effects on heart rate
Demont, Emmanuel H.,Andrews, Benjamin I.,Bit, Rino A.,Campbell, Colin A.,Cooke, Jason W. B.,Deeks, Nigel,Desai, Sapna,Dowell, Simon J.,Gaskin, Pam,Gray, James R. J.,Haynes, Andrea,Holmes, Duncan S.,Kumar, Umesh,Morse, Mary A.,Osborne, Greg J.,Panchal, Terry,Patel, Bela,Perboni, Alcide,Taylor, Simon,Watson, Robert,Witherington, Jason,Willis, Robert
supporting information; experimental part, p. 444 - 449 (2011/08/08)
Gilenya (fingolimod, FTY720) was recently approved by the U.S. FDA for the treatment of patients with remitting relapsing multiple sclerosis (RRMS). It is a potent agonist of four of the five sphingosine 1-phosphate (S1P) G-protein-coupled receptors (S1P1 and S1P3-5). It has been postulated that fingolimod's efficacy is due to S1P1 agonism, while its cardiovascular side effects (transient bradycardia and hypertension) are due to S1P3 agonism. We have discovered a series of selective S1P 1 agonists, which includes 3-[6-(5-{3-cyano-4-[(1-methylethyl)oxy] phenyl}-1,2,4-oxadiazol-3-yl)-5-methyl-3,4-dihydro-2(1H)-isoquinolinyl] propanoate, 20, a potent, S1P3-sparing, orally active S1P1 agonist. Compound 20 is as efficacious as fingolimod in a collagen-induced arthritis model and shows excellent pharmacokinetic properties preclinically. Importantly, the selectivity of 20 against S1P3 is responsible for an absence of cardiovascular signal in telemetered rats, even at high dose levels.
PESTICIDAL CARBOXAMIDES
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Page/Page column 74, (2011/02/24)
The object of the present invention is to provide novel carboxamides which exhibit an excellent pesticidal activity as pesticides. Disclosed are the carboxamides represented by the following Formula (I) wherein each substituent is as defined in the specif
S1P1 AGONISTS COMPRISING A BICYCLIC N-CONTAINING RING
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Page/Page column 98, (2010/12/31)
The present invention relates to novel compounds of formula (I) having S1P1 agonist activity, processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of various disorders.
PYRIMIDINONES AS CASEIN KINASE II (CK2) MODULATORS
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Page/Page column 46, (2009/01/20)
A compound having Formula I :or a pharmaceutically acceptable salt thereof, wherein X, R, R and R are as defined in the specification; pharmaceutical compositions thereof; and methods of use thereof. The compounds of Fomula I are inhibitors of Casein kina
