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Through virtual screening, we identified the lead compound MCL1020, which exhibited modest CHK1 inhibitory activity. Then a series of 5-(pyrimidin-2-ylamino)picolinonitrile derivatives as CHK1 inhibitors were discovered by further rational optimization. One promising molecule, (R)-17, whose potency was one of the best, had an IC of 0.4 nM with remarkable selectivity (>4300-fold CHK1 vs. CHK2). Compound (R)-17 effectively inhibited the growth of malignant hematopathy cell lines especially Z-138 (
0.013 μM) and displayed low affinity for hERG (IC > 40 μM). Moreover, (R)-17 significantly suppressed the tumor growth in Z-138 cell inoculated xenograft model (20 mg/kg I.V., TGI = 90.29%) as a single agent with body weight unaffected. Taken together, our data demonstrated compound (R)-17 could be a promising drug candidate for the treatment of hematologic malignancies.
This article was published in the following journal.
Name: European journal of medicinal chemistry
A series of ferrocenes which contain dinitrogen-fused pyrazolidinone ring were synthesized from acryloylferrocene (4) and N,N'‑cyclic azomethine imines (3). Novel 5‑aryl‑6‑ferrocenoyltetrahydr...
Discovery and Development of N-4-(l-Cyclobutylpiperidin-4-yloxy) phenyl-2-(morpholin-4-yl) acetamide dihydrochloride (SUVN-G3031): A Novel, Potent, Selective and Orally Active Histamine H3 Receptor Inverse Agonist with Robust Wake-Promoting Activity.
A series of chemical optimizations guided by in vitro affinity at histamine H3 receptor (H3R), physico-chemical properties and pharmacokinetics in rats resulted in identification of N-[4-(1-Cyclobutyl...
Concurrent inhibition of JAK and HDAC could potentially improve the efficacy of the HDAC inhibitors in the treatment of cancers and resolve the problem of HDAC inhibitor resistance in some tumors. Her...
Escherichia coli expression protocols for selective labeling of methyl groups in proteins have been essential in expanding the size range of targets that can be studied by biomolecular NMR. Based on t...
Graph theoretical analysis, in silico modeling, prediction of toxicity, metabolism and synthesis of novel 2-(methyl/phenyl)-3-(4-(5-substituted-1,3,4-oxadiazol-2-yl) phenyl) quinazolin-4(3H)-ones as NMDA receptor inhibitor.
Hit, Lead & Candidate Discovery A variety of novel 2-(methyl/phenyl)-3-(4-(5-substituted-1,3,4-oxadiazol-2-yl)phenyl) quinazolin-4(3H)-ones have been synthesized by treating 3-(4-(5-mercapto-1,3,4-oxa...
The primary objective of this study in adults with advanced or recurrent solid tumors or lymphoma is to evaluate the safety and tolerability of AR-12 by describing dose-limiting toxicities...
The proposed study will assess the combined effect of perampanel and ketamine on the anti-depressant response in individuals with treatment resistant depression. The purpose of this study ...
Adjuvant N-methyl-D-aspartic acid (NMDA)-enhancing agents, such as GlyT-1 inhibitors and NMDA-glycine site agonists have been demonstrated to be beneficial for chronic schizophrenia patien...
This extended access study will assess the long-term safety and tolerability of bardoxolone methyl in qualified patients with chronic kidney disease (CKD) who previously participated in on...
The purpose of this prospective clinical trial is to document the performance and clinical outcomes of Biomet Discovery Elbow.
1-Deoxy-1-(methylamino)-D-glucitol. A derivative of sorbitol in which the hydroxyl group in position 1 is replaced by a methylamino group. Often used in conjunction with iodinated organic compounds as contrast medium.
3-((4-Amino-2-methyl-5-pyrimidinyl)methyl)-5-(2- hydroxyethyl)-4-methylthiazolium chloride.
3-((4-Amino-2-methyl-5-pyrimidinyl)methyl)-4-methyl-5-(4,6,8,8-tetrahydroxy-3,5,7-trioxa-4,6,8-triphosphaoct-1-yl)thiazolium hydroxide, inner salt, P,P',P''-trioxide. The triphosphate ester of thiamine. In Leigh's disease, this compound is present in decreased amounts in the brain due to a metabolic block in its formation.
The D-enantiomer is a potent and specific antagonist of NMDA glutamate receptors (RECEPTORS, N-METHYL-D-ASPARTATE). The L form is inactive at NMDA receptors but may affect the AP4 (2-amino-4-phosphonobutyrate; APB) excitatory amino acid receptors.
Toluenes in which one hydrogen of the methyl group is substituted by an amino group. Permitted are any substituents on the benzene ring or the amino group.
Pharmacy is the science and technique of preparing as well as dispensing drugs and medicines. It is a health profession that links health sciences with chemical sciences and aims to ensure the safe and effective use of pharmaceutical drugs. The scope of...