638219-77-9Relevant academic research and scientific papers
Identification of 2-Aminopyrimidine Derivatives as FLT3 Kinase Inhibitors with High Selectivity over c-KIT
Tong, Lexian,Wang, Peipei,Li, Xuemei,Dong, Xiaowu,Hu, Xiaobei,Wang, Chang,Liu, Tao,Li, Jia,Zhou, Yubo
, p. 3229 - 3248 (2022/02/23)
Herein, we report two promising compounds 30 and 36 possessing nanomolar FLT3 inhibitory activities (IC50 = 1.5-7.2 nM), high selectivity over c-KIT (>1000-fold), and excellent anti-AML activity (MV4-11 IC50 = 0.8-3.2 nM). Furthermore, these two compounds efficiently inhibited the growth of multiple mutant BaF3 cells expressing FLT3-ITD, FLT3-D835V/F, FLT3-F691L, FLT3-ITD-F691L, and FLT3-ITD-D835Y. Oral administration of 30 and 36 at 6 mg/kg/d could significantly suppress tumor growth in the MV4-11 cell-inoculated xenograft model, exhibiting tumor growth inhibitory rates of 83.5% and 95.1%, respectively. Importantly, 36 could prolong the mouse survival time in the FLT3-ITD-TKD dual mutation syngeneic mouse model (BaF3-FLT3-ITD-D835Y) at a dose of 6 mg/kg p.o. bid/4W. No clear myelosuppression was observed in the treated group of 36 in the MPO strain of zebrafish, even at 10 μM. In summary, our data demonstrated that 36 may represent a promising candidate for the treatment of FLT3 mutant AML.
N2-carbamylaryl-2-aminopyrimidine derivative and medical application thereof
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Paragraph 0037; 0040-0041; 0045, (2020/10/28)
The invention provides an N2-carbamylaryl-2-aminopyrimidine derivative and a medical application thereof. The N2-carbamylaryl-2-aminopyrimidine derivative provided by the invention comprises an optical isomer of the N2-carbamylaryl-2-aminopyrimidine derivative and pharmaceutically acceptable salt thereof. Pharmacodynamic research shows that the traditional Chinese medicine composition has no toxicor side effect, the compound has an FLT3 inhibitory activity. The proliferation inhibition activity is realized on various leukemia cell strains; a medium inhibition effect is achieved on breast cancer cells; moreover, the polypeptide is effective for multiple mutations of AML, such as internal tandem repeat mutation of a near-membrane structural domain and D835 point mutation of an activated ring in a kinase structural domain, almost has no inhibition effect on c-KIT, can overcome drug resistance brought by clinical point mutation, can reduce toxic and side effects of bone marrow inhibition,and can be applied to preparation of antitumor drugs. The structures of the general formulas Ia and Ib of the N2-carbamylaryl-2-aminopyrimidine derivative are shown in the specification,
Design, synthesis, and biological evaluation of 8-biarylquinolines: A novel class of PDE4 inhibitors
Gallant, Michel,Chauret, Nathalie,Claveau, David,Day, Stephen,Deschenes, Denis,Dube, Daniel,Huang, Zheng,Lacombe, Patrick,Laliberte, France,Levesque, Jean-Francois,Liu, Susana,Macdonald, Dwight,Mancini, Joseph,Masson, Paul,Mastracchio, Anthony,Nicholson, Donald,Nicoll-Griffith, Deborah A.,Perrier, Helene,Salem, Myriam,Styhler, Angela,Young, Robert N.,Girard, Yves
, p. 1407 - 1412 (2008/12/22)
The structure-activity relationship of a novel series of 8-biarylquinolines acting as type 4 phosphodiesterase (PDE4) inhibitors is described herein. Prototypical compounds from this series are potent and non-selective inhibitors of the four distinct PDE4 (IC50 50 0.5 μM) the LPS-induced release of the cytokine TNF-α. Optimized inhibitors were evaluated in vivo for efficacy in an ovalbumin-induced bronchoconstriction model in conscious guinea pigs. Their propensity to produce an emetic response was evaluated by performing pharmacokinetic studies in squirrel monkeys. This work has led to the identification of several compounds with excellent in vitro and in vivo profiles, including a good therapeutic window of efficacy over emesis.
8-(BIARYL) QUINOLINE PDE4 INHIBITORS
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Page 69, (2010/02/06)
8-(biaryl) quinolines wherein the bi-aryl group at the 8-position is in a meta relationship to the quinoline group, are PDE4 inhibitors useful in the treatment of asthma, chronic bronchitis, chronic obstructive pulmonary disease, eosinophilic granuloma, psoriasis and other benign or malignant proliferative skin diseases, endotoxic shock, laminitis in horses, colic in horses, septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, inflammatory arthritis, chronic glomerulonephritis, atopic dermatitis, urticaria, adult respiratory distress syndrome, chronic obstructive pulmonary disease in animals, diabetes insipidus, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, arterial restenosis, ortherosclerosis, atherosclerosis, neurogenic inflammation, pain, cough, rheumatoid arthritis, ankylosing spondylitis, transplant rejection, graft versus host disease, hypersecretion of gastric acid, bacterial, fungal induced sepsis, viral induced sepsis, fungal induced septic shock, viral induced septic shock, inflammation-mediated chronic tissue degeneration, cytokine-mediated chronic tissue degeneration, osteoarthritis, cancer, cachexia, muscle wasting, depression, memory impairment, tumour growth, or cancerous invasion of normal tissues.In another aspect, the present invention is directed to a method of enhancing cognition in a healthy subject comprising administering a safe cognition enhancing amount of phosphodiesterase-4 inhibitor. In particular, this invention is directed to a method of enhancing memory, learning, retention, recall, awareness and judgement in health subjects comprising administering a safe and cognition enhancing amount of a phosphodiesterase-4 inhibitor.
