Intravitreal injection therapy of anti-vascular endothelial growth factor (VEGF) antibody or steroids is the mainstream for patients with age-related macular degeneration (AMD). However, since intravitreal injection is invasive administration, side effects such as endophthalmitis are major problems. In this study, we selected eye drops as a non-invasive treatment method, and aimed to develop eye drops that can deliver TAK-593 (VEGF receptor tyrosine kinase inhibitor) to the posterior segment of the eye. Since TAK-593 is a poorly water-soluble drug, the TAK-593 emulsion was formulated. The solubility of TAK-593 in various oils was measured, and the oil used for the emulsion was selected. Furthermore, viscosity enhancers were added to the emulsion in order to improve the drug delivery into the eye. As viscosity enhancer, xanthan gum was selected based on the properties and the viscosity of the emulsion. The delivery of TAK-593 to the posterior eye was increased by the formulation concentration and the addition of viscosity enhancers. In the laser-induced choroidal neovascularization model, TAK-593 emulsion eye drops showed the same angiogenesis-suppression efficacy as anti-VEGF antibody intravitreal injection. From these results, it was revealed that TAK-593 with an effective drug concentration can be delivered to the posterior eye by non-invasive eye drop administration.

2013-04-01·Bioorganic & Medicinal Chemistry3区 · 医学

Discovery of N -[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2- b ]pyridazin-6-yl}oxy)-2-methylphenyl]-1,3-dimethyl-1 H -pyrazole-5-carboxamide (TAK-593), a highly potent VEGFR2 kinase inhibitor

3区 · 医学

Article

作者: Hori, Akira ; Takagi, Terufumi ; Hirayama, Takaharu ; Miyamoto, Naoki ; Miki, Hiroshi ; Takeuchi, Toshiyuki ; Awazu, Yoshiko ; Oguro, Yuya ; Sakai, Nozomu ; Imamura, Shinichi ; Miwa, Kazuhiro ; Okada, Kengo ; Iwata, Hidehisa ; Oki, Hideyuki ; Yamasaki, Seiji

Vascular endothelial growth factor (VEGF) plays important roles in tumor angiogenesis, and the inhibition of its signaling pathway is considered an effective therapeutic option for the treatment of cancer. In this study, we describe the design, synthesis, and biological evaluation of 2-acylamino-6-phenoxy-imidazo[1,2-b]pyridazine derivatives. Hybridization of two distinct imidazo[1,2-b]pyridazines 1 and 2, followed by optimization led to the discovery of N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide (23a, TAK-593) as a highly potent VEGF receptor 2 kinase inhibitor with an IC50 value of 0.95 nM. The compound 23a strongly suppressed proliferation of VEGF-stimulated human umbilical vein endothelial cells with an IC50 of 0.30 nM. Kinase selectivity profiling revealed that 23a inhibited platelet-derived growth factor receptor kinases as well as VEGF receptor kinases. Oral administration of 23a at 1 mg/kg bid potently inhibited tumor growth in a mouse xenograft model using human lung adenocarcinoma A549 cells (T/C=8%).

2011-02-08·Biochemistry3区 · 生物学

Biochemical Characterization of TAK-593, a Novel VEGFR/PDGFR Inhibitor with a Two-Step Slow Binding Mechanism

3区 · 生物学

Article

作者: Hori, Akira ; Miki, Hiroshi ; Hixon, Mark S. ; Iwata, Hidehisa ; Kimura, Hiroyuki ; Imamura, Shinichi

Inhibition of tumor angiogenesis leads to a lack of oxygen and nutrients in the tumor and therefore has become a standards of care for many solid tumor therapies. Dual inhibition of vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) protein kinase activities is a popular strategy for targeting tumor angiogenesis. We discovered that TAK-593, a novel imidazo[1,2-b]pyridazine derivative, potently inhibits tyrosine kinases from the VEGFR and PDGFR families. TAK-593 was highly selective for these families, with an IC(50) >1 μM when tested against more than 200 protein and lipid kinases. TAK-593 displayed competitive inhibition versus ATP. In addition, TAK-593 inhibited VEGFR2 and PDGFRβ in a time-dependent manner, classifying it as a type II kinase inhibitor. Analysis of enzyme-inhibitor preincubation experiments revealed that the binding of TAK-593 to VEGFR2 and PDGFRβ occurs via a two-step slow binding mechanism. Dissociation of TAK-593 from VEGFR2 was extremely slow (t(1/2) >17 h), and the affinity of TAK-593 at equilibrium (K(i)*) was less than 25 pM. Ligand displacement analysis with a fluorescent tracer confirmed the slow dissociation of TAK-593. The dissociation rate constants were in good agreement between the activity and ligand displacement data, and both analyses supported slow dissociation of TAK-593. The long residence time of TAK-593 may achieve an extended pharmacodynamic effect on VEGFR2 and PDGFRβ kinases in vivo that differs substantially from its observed pharmacokinetic profile.

100 项与 TAK-593 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB13093

研发状态

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适应症	最高研发状态	国家/地区	公司	日期
晚期癌症	临床1期	美国	Millennium Pharmaceuticals, Inc.	2009-01-01
肿瘤	临床1期	-	Takeda Pharmaceutical Co., Ltd.	-
实体瘤	临床1期	美国	Millennium Biotechnologies, Inc.	-
实体瘤	临床1期	美国	Millennium Biotechnologies, Inc.	-