Discovery of 4-(4-aminopyrazolo[1,5-a][1,3,5]triazin-8-yl) benzamides as novel, highly potent and selective, orally bioavailable inhibitors of Tyrosine Threonine Kinase, TTK

Laufer Radoslaw; Li Sze-Wan; Liu Yong; Ng Grace; Lang Yunhui; Feher Miklos; Brokx Richard; Beletskaya Irina; Hodgson Richard; Mao Guodong; Plotnikova Olga; Awrey Donald E.; Mason Jacqueline M.; Wei Xin; Lin Dan Chi-Chia; Che Yi; Kiarash Reza; Madeira Brian; Fletcher Graham C.; Mak Tak W.; Bray Mark R.; Pauls Henry W.

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Discovery of 4-(4-aminopyrazolo[1,5-a][1,3,5]triazin-8-yl) benzamides as novel, highly potent and selective, orally bioavailable inhibitors of Tyrosine Threonine Kinase, TTK

机译：发现4-（4-氨基吡唑并[1,5-a] [1,3,5]三嗪-8-基）苯甲酰胺是新型，高效且选择性的酪氨酸苏氨酸激酶，TTK口服生物利用抑制剂

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TTK/Mps1 is a key kinase controlling progression of cell division via participation in the mitotic spindle assembly checkpoint and is overexpressed in a number of human cancers. Herein we report the discovery of 4-(4-aminopyrazolo[1,5-a][1,3,5]triazin-8-yl) benzamides as a potent, novel class of TTK inhibitors. The series was identified by means of bioisosteric replacement of the related imidazopyrazine and imida-zopyridazine scaffolds. Optimization led to the identification of compounds with excellent potency (K-i = 0.8 nM) and exceptional kinase selectivity. The SAR indicates a strong dependence of activity on the presence of the N-cyclopropyl-2-methylbenzamide moiety delineating the geometry for 11/2 type kinase inhibitor. Molecular modeling indicates the extensive and optimal contacts, mediated through H-bonds and hydrophobic interactions, are responsible for the selectivity and potency of the inhibitors. The compounds demonstrate a strong anti-proliferative activity in a panel of human cancer cell lines (HCT116 GI(50) < 15 nM) and good rodent pharmacokinetics (oral %F 97%). (C) 2016 Elsevier Ltd. All rights reserved.

机译：TTK / Mps1是通过参与有丝分裂纺锤体装配检查点来控制细胞分裂进程的关键激酶，在许多人类癌症中均过表达。在本文中，我们报告了作为有效的新型TTK抑制剂的4-（4-氨基吡唑并[1,5-a] [1,3,5]三嗪-8-基）苯甲酰胺的发现。该系列通过相关等价的咪唑并吡嗪和咪唑并哒哒嗪支架的生物立体置换来鉴定。通过优化，鉴定出具有出色效价（K-i = 0.8 nM）和出色的激酶选择性的化合物。 SAR表明活性强烈依赖于N-环丙基-2-甲基苯甲酰胺部分的存在，该部分描述了11/2型激酶抑制剂的几何形状。分子建模表明，通过氢键和疏水相互作用介导的广泛和最佳接触是抑制剂的选择性和效力的原因。这些化合物在一组人类癌细胞系（HCT116 GI（50）<15 nM）中显示出强大的抗增殖活性，并具有良好的啮齿动物药代动力学（口服％F 97％）。（C）2016 Elsevier Ltd.保留所有权利。

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《Bioorganic and Medicinal Chemistry Letters》 |2016年第15期|共5页
作者
Laufer Radoslaw; Li Sze-Wan; Liu Yong; Ng Grace; Lang Yunhui; Feher Miklos; Brokx Richard; Beletskaya Irina; Hodgson Richard; Mao Guodong; Plotnikova Olga; Awrey Donald E.; Mason Jacqueline M.; Wei Xin; Lin Dan Chi-Chia; Che Yi; Kiarash Reza; Madeira Brian; Fletcher Graham C.; Mak Tak W.; Bray Mark R.; Pauls Henry W.;
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Tyrosine Threonine Kinase (TTK); Monopolar spindle 1 kinase (Mps1); Antimitotic; Inhibitor; Cancer;

机译：酪氨酸苏氨酸激酶（TTK）;单极纺锤体1激酶（Mps1）;抗有丝分裂;抑制剂;癌症;

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1. Discovery of 4-(4-aminopyrazolo[1,5-a][1,3,5]triazin-8-yl) benzamides as novel, highly potent and selective, orally bioavailable inhibitors of Tyrosine Threonine Kinase, TTK [J] . Laufer Radoslaw, Li Sze-Wan, Liu Yong, Bioorganic and Medicinal Chemistry Letters . 2016,第15期

机译：发现4-（4-氨基吡唑并[1,5-a] [1,3,5]三嗪-8-基）苯甲酰胺是新型，高效且选择性的酪氨酸苏氨酸激酶，TTK口服生物利用抑制剂
2. Discovery of N?((4-([1,2,4]Triazolo[1,5?a]pyridin-6-yl)-5- (6-methylpyridin-2-yl)?1H?imidazol-2-yl)methyl)-2-fluoroaniline (EW-7197): A Highly Potent, Selective, and Orally Bioavailable Inhibitor of TGF?β Type I Receptor Kinase as Cancer Immunotherapeutic/Antifibrotic Agent [J] . Cheng Hua Jin, Maddeboina Krishnaiah, Domalapally Sreenu, Journal of Medicinal Chemistry . 2014,第10期

机译：N？（（4-（[1,2,4] Triazolo [1,5？a]吡啶-6-基）-5-（6-甲基吡啶-2-基）？1H？咪唑-2-基的发现）甲基）-2-氟苯胺（EW-7197）：TGF？βI型受体激酶的高效，选择性和口服生物利用抑制剂，可作为癌症免疫治疗/抗纤维化剂
3. Discovery of N-(3-(5-((3-acrylamido-4-(morpholine-4-carbonyl) phenyl)amino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-methylphenyl)-4-(tert-butyl)benzamide (CHMFL-BTK-01) as a highly selective irreversible Bruton's tyrosine kinase (BTK) inhibitor [J] . Liang Qianmao, Chen Yongfei, Yu Kailin, European Journal of Medicinal Chemistry: Chimie Therapeutique . 2017,第期

机译：发现N-（3-（5 - （（3-丙基-4-（吗啉-4-羰基）苯基）氨基）-1-甲基-6-氧代-1,6-二氢吡啶-3-Y1）-2 - 甲基苯基）-4-（叔丁基）苯甲酰胺（CHMFL-BTK-01）作为高选择性不可逆的Bruton的酪氨酸激酶（BTK）抑制剂
4. CNX-774, an Irreversible, Selective and Orally Bioavailable Inhibitor of Bruton's Tyrosine Kinase: In Vitro ADME, Selectivity, and Pharmacokinetic Properties [C] . Prasoon Chaturvedi, Matthew Labenski, Erica Evans, American Society for Mass Spectrometry Conference on Mass Spectrometry and Allied Topics . 2011

机译：CNX-774，Bruton的酪氨酸激酶的不可逆转，选择性和口服生物可利用的抑制剂：体外Adme，选择性和药代动力学性能
5. Pharmacological Characterization of TAS05567, a Potent and Selective Inhibitor of Spleen Tyrosine Kinase, in Animal Models of Inflammatory Diseases and B-cell Malignancies [D] . 林宏明 2019

机译：TAS05567，脾酪氨酸激酶的强效和选择性抑制剂，在炎症性疾病和B细胞恶性动物模型中的药理特性
6. Discovery of Potent Orally Active Compounds of Tyrosine Kinase and Serine/Threonine-Protein Kinase Inhibitor With Anti-Tumor Activity in Preclinical Assays [O] . Yun-Qing Qiu, Jue Zhou, Xin-Shan Kang, 2012

机译：在临床前测定中发现具有酪氨酸活性的酪氨酸激酶和丝氨酸/苏氨酸蛋白激酶抑制剂的有效口服活性化合物
7. Discovery of Potent, Highly Selective, and Orally Bioavailable Pyridine Carboxamide c-Jun NH2-Terminal Kinase Inhibitors [O] . -1

机译：发现有效，高精度，口服生物可利用的吡啶羧酰胺C-Jun NH2末端激酶抑制剂

Discovery of 4-(4-aminopyrazolo[1,5-a][1,3,5]triazin-8-yl) benzamides as novel, highly potent and selective, orally bioavailable inhibitors of Tyrosine Threonine Kinase, TTK

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