137583-05-2Relevant articles and documents
From Experiments to a Fast Easy-to-Use Computational Methodology to Predict Human Aldehyde Oxidase Selectivity and Metabolic Reactions
Cruciani, Gabriele,Milani, Nicolò,Benedetti, Paolo,Lepri, Susan,Cesarini, Lucia,Baroni, Massimo,Spyrakis, Francesca,Tortorella, Sara,Mosconi, Edoardo,Goracci, Laura
, p. 360 - 371 (2018)
Aldehyde oxidase (AOX) is a molibdo-flavoenzyme that has raised great interest in recent years, since its contribution in xenobiotic metabolism has not always been identified before clinical trials, with consequent negative effects on the fate of new potential drugs. The fundamental role of AOX in metabolizing xenobiotics is also due to the attempt of medicinal chemists to stabilize candidates toward cytochrome P450 activity, which increases the risk for new compounds to be susceptible to AOX nucleophile attack. Therefore, novel strategies to predict the potential liability of new entities toward the AOX enzyme are urgently needed to increase effectiveness, reduce costs, and prioritize experimental studies. In the present work, we present the most up-to-date computational method to predict liability toward human AOX (hAOX), for applications in drug design and pharmacokinetic optimization. The method was developed using a large data set of homogeneous experimental data, which is also disclosed as Supporting Information.
Development of dual inhibitors targeting pyruvate dehydrogenase kinases and human lactate dehydrogenase A: High-throughput virtual screening, synthesis and biological validation
Xiang, Sichuan,Huang, Ding,He, Qiaolin,Li, Jie,Tam, Kin Yip,Zhang, Shao-Lin,He, Yun
supporting information, (2020/07/21)
Most cancer cells feature an altered glucose metabolism from oxidative phosphorylation to cytoplasmic glycolysis. Pyruvate dehydrogenase kinases (PDKs) and lactate dehydrogenase A (LDHA) play crucial roles in promotion of glycolysis, thus the inhibition of both enzymes is considered a promising strategy for developing of anticancer therapeutics. Herein, we describe the first discovery of series novel dual inhibitors targeting PDKs and LDHA. We identified 6 hits from a library database containing 485465 compounds through a high-throughput virtual screening assay. Hit-to-lead optimization enabled us to discover two compounds, namely 20e and 20k, which inhibited PDKs with IC50 values of 0.8, and 1.6 μM, respectively, and inhibited LDHA with IC50 values of 0.15 and 0.7 μM, respectively. Meanwhile, the two compounds reduced A549 cell proliferation with EC50 values of 13.2, and 15.7 μM. Furthermore, 20e and 20k decreased the lactate formation, and increased oxygen consumption, suggesting the two compounds modulated the glucose metabolic pathways in cancer cells.
SUBSTITUTED 2H-[1,2,4]TRIAZOLO[4,3-A]PYRAZINES AS GSK-3 INHIBITORS
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Page/Page column 27, (2010/02/11)
The invention relates to compounds of formula (I) prodrugs thereof, and the pahrmaceutically acceptabel salts of the compounds and prodrugs, wherein Ra, Rb, R1 and R2 are as defined herein; pharmaceutical compositions thereof; and uses thereof.
PYRAZOLOPYRIMIDINES AS CYCLIN-DEPENDENT KINASE INHIBITORS
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Page 93, (2008/06/13)
In its many embodiments, the present invention provides a novel class of pyrazolo[1,5-a]pyrimidine compounds as inhibitors of cyclin dependent kinases, methods of preparing such compounds, pharmaceutical compositions containing one or more such compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention, inhibition, or amelioration of one or more diseases associated with the CDKs using such compounds or pharmaceutical compositions.
Substituted 4-amino[1,2,4]triazolo[4,3-a] quinoxalines
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Page/Page column 12, (2010/02/08)
The present invention provides compounds of formula (I) the prodrugs thereof, and the pharmaceutically acceptable salts of the compounds and prodrugs, wherein Ra, Rb, R1, and R2 are as defined herein; pharmaceutical compositions thereof; and uses thereof.
Vitronectin receptor antagonists
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, (2008/06/13)
PCT No. PCT/US96/20327 Sec. 371 Date Jul. 27, 1999 Sec. 102(e) Date Jul. 27, 1999 PCT Filed Dec. 20, 1996 PCT Pub. No. WO97/24124 PCT Pub. Date Jul. 10, 1999Compounds of formula (I) are disclosed, wherein: A is a fibrinogen antagonist template; W is a linking moiety of the form -(CHRg)a-U-(CHRg)b-V-; Q1, Q2, Q3 and Q4 are independently N or C-Ry, provided that no more than one Q1, Q2, Q3 and Q4 is N; R' is H or C1-6alkyl, C3-7cycloalkyl-C0-6-alkyl or Ar-C0-6alkyl; Rg is H or C1-6alkyl, Het-C0-6alkyl, C3-7cycloalkyl-C0-6alkyl or Ar-C0-6alkyl; Rk is Rg, -C(O)Rg or -C(O)ORg Ri is H, C1-6alkyl, Het-C0-6alkyl, C3-7cycloalkyl-C0-6alkyl, Ar-C0-6alkyl, Het-C0-6alkyl-U'-C1-6alkyl, C3-7cycloalkyl-C0-6alkyl-U'-C1-6alkyl or Ar-C0-6alkyl-U'-C1-6alkyl; Ry is H, halo, -ORg, -SRg, -CN, -NRgRk, -NO2, -CF3, CF3S(O)r, -CO2Rg, -CORg or -CONRg2, or C1-6alkyl optionally substituted by halo, -ORg, -SRg, -CN, -NR8R'', -NO2, -CF3, R'S(O)3-, -CO2Rg, -CORg or -CONRg2; U and V are absent or CO, CRg2, C(=CRg2), S(O)c, O, NRg, CRgORg, CRg(ORk)CRg2, CRg7CRg(ORk), C(O)CRg2, CRg2C(O), CONRi, NRiCO, OC(O), C(O)O, OC(S), C(S)NRg, NR8C(S), S(O2NRg, NRgS(O)2N=N, NRgNRg, NRgCRg2, NRgCRg2, CRg2O, OCRg2, CRg=CRg, C=C, Ar or Het; a is 0, 1 or 2; c is 0, 1 or 2; r is 0, 1 or 2; and u is 0 or 1; or pharmaceutically acceptable salts thereof, which are vitronectin receptor antagonists useful in the treatment of osteoporosis.
Class III Antiarrhythmic Activity of Novel Substituted 4-benzamides and Sulfonamides
Ellingboe, John W.,Spinelli, Walter,Winkley, Michael W.,Nguyen, Thomas T.,Parsons, Roderick W.,et al.
, p. 705 - 716 (2007/10/02)
The synthesis and Class III antiarrhythmic activity of a series of 4-benzamides and sulfonamides are described.Selected compounds shown a potent Class III activity and are devoid of effects on conduction both in vitro (dog Purkinje fibers) and in vivo (anesthetized dogs).Compounds having a 2-aminobenzimidazole group were found to be the most potent, and one compound having the heterocycle (5, WAY-123,398) was selected for further characterization.Compound 5 was shown to have good oral bioavailability and a favorable hemodynamic profile to produce a 3-fold increase of the ventricular fibrillation threshold and to terminate ventricular fibrillation, restoring sinus rhythm in anesthetized dogs.Voltage-clamp studies in isolated myocytes show that 5 is a potent and specific blocker of the delayed rectifier potassium current (IK) at concentrations that cause significant prolongation of action potential duration.