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Thursday, 21 November 2013

TAK 593

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

 Original Research Article
Pages 2333-2345
Naoki Miyamoto, Nozomu Sakai, Takaharu Hirayama, Kazuhiro Miwa, Yuya Oguro, Hideyuki Oki, Kengo Okada, Terufumi Takagi, Hidehisa Iwata, Yoshiko Awazu, Seiji Yamasaki, Toshiyuki Takeuchi, Hiroshi Miki, Akira Hori, Shinichi Imamura

Graphical abstract

.................. PAPER describes 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%).

Full-size image (20 K)
Reagents: (a) ethyl (chloroacetyl)carbamate, Na2HPO4, DMA; (b) Ba(OH)2, NMP/H2O; (c) R1COCl, DMA; (d) 3-aminophenol, K2CO3, DMF; (e) 3-fluorobenzoyl chloride, DMA.


 TAK-593 is an oral formulation containing a small-molecule receptor tyrosine kinase inhibitor of both vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) with potential antineoplastic activity. TAK-593 selectively binds to and inhibits VEGFR and PDGFR, which may result in the inhibition of angiogenesis and tumor cell proliferation. Check for active clinical trials or closed clinical trials using this agent.

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. (source: Biochemistry. 2011 Feb 8;50(5):738-51. Epub 2011 Jan 10.). 

TAK-493 is  currently in Phase I clinical trials and is being developed by Millennium Pharmaceuticals, Inc. (a part of Takeda Pharmaceutical Company Limited).
 1. Biochemical Characterization of TAK-593, a Novel VEGFR/PDGFR Inhibitor with a Two-Step Slow Binding Mechanism. By Iwata, Hidehisa; Imamura, Shinichi; Hori, Akira; Hixon, Mark S.; Kimura, Hiroyuki; Miki, Hiroshi. From Biochemistry (2011), 50(5), 738-751.

2. Fused heterocyclic derivatives as kinase inhibitors and their preparation, pharmaceutical compositions and use in the treatment of cancer. By Sakai, Nozomu; Imamura, Shinichi; Miyamoto, Naoki; Hirayama, Takaharu. From PCT Int. Appl. (2008), WO 2008016192 A2 20080207.

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