Isoindolinone ureas: a novel class of KDR kinase inhibitors Michael L. Curtin, a, * Robin R. Frey, a H. Robin Heyman, a Kathy A. Sarris, a Douglas H. Steinman, a James H. Holmes, a Peter F. Bousquet, b George A. Cunha, b Maria D. Moskey, b Asma A. Ahmed, b Lori J. Pease, a Keith B. Glaser, a Kent D. Stewart, a Steven K. Davidsen a and Michael R. Michaelides a a Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-6100, USA b Global Pharmaceutical Research and Development, Abbott Bioresearch Center, 100 Research Drive, Worcester, MA 01605-5314, USA Received 19 May 2004; revised 14 June 2004; accepted 14 June 2004 Available online 6 July 2004 Abstract—A series of substituted isoindolinone ureas was prepared and evaluated for enzymatic and cellular inhibition of KDR kinase activity. Several of these analogs, such as 14c, are potent inhibitors of KDR both enzymatically (<50nM) and cellularly ( 6100nM). A 3D KDR/CDK2/MAP kinase overlay model with several structurally related tyrosine kinase inhibitors was used to predict the binding interactions of the isoindolinone ureas with the KDR active site. Ó 2004 Elsevier Ltd. All rights reserved. Reversible protein phosphorylation by protein kinases is one of the primary biochemical mechanisms mediating eukaryotic cell signaling. 1 A subset of these kinases, the receptor tyrosine kinases (RTKs), possess both extra- cellular and intracellular domains and selectively cata- lyze the phosphorylation of tyrosine hydroxyl groups in response to binding of certain extracellular growth fac- tors. 2 RTK signaling pathways are normally highly regulated, yet their overactivation has been shown to promote the growth, survival, and metastasis of cancer cells and has been associated with the progression of various human cancers. 3 The VEGF receptor family of RTKs, most notably VEGFR2 or KDR, mediates the biologicalfunctionofvascularendothelialgrowthfactor (VEGF), which is a regulator of vascular permeability and an inducer of endothelial cell proliferation, migra- tion, and survival. 4 Accordingly, interruption of the KDR mediated signaling cascade can provide an anti- angiogenic effect in human cancers as recently demon- strated by the FDA approval of the anti-VEGF antibody Avastin e for the treatment of colorectal cancer. 5 In addition, several small-molecule KDR kinase inhibitors have been shown to be efficacious in in vivo tumor xenograft models and have entered cancer clinical trials. 6 In an ongoing effort at Abbott Laboratories to develop small-molecule RTK inhibitors, it was recently dis- closed 7 that the diphenyl urea of LCK kinase inhibitor pyrazolopyrimidine 1a greatly enhanced KDR potency (KDR IC 50 ¼ 263nM) 8 versus related analogs such as phenyl amide 1b (KDR IC 50 >50 lM). This is consistent with earlier observations 9 that variously substituted bis- aryl ureas were potent against a number of protein ki- nasesincludingp38MAP,RAF-1,andtheCDKs.Inan effort to design novel inhibitors of KDR, we believed that the adenine-like pyrrolopyrimidine nucleus of 1 could be replaced with other polycyclic, aromatic sys- tems, which would be capable of making several key hydrogen bond interactions, which are common among ATP-competitive kinase inhibitors. 10 One such nucleus is the isoindolinone of the broad spectrum kinase inhibitor staurosporine 11 (2,KDRIC 50 ¼ 115nM 8 ) and, more recently, KDR inhibitor CEP-7055 12 (3, KDR IC 50 ¼ 18nM 13 ). 14 Initial modeling of the various re- gioisomers of diphenyl urea-substituted isoindolinone with KDR indicated that regioisomer 4a (rings labeled for clarity) could be a viable inhibitor; this idea was validated by the fact that 4a possessed inhibitory Keywords: KDR kinase; VEGF; Isoindolinone; Urea. *Corresponding author. Tel.: +1-847-9380463; fax: +1-847-9355165; e-mail: mike.curtin@abbott.com 0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2004.06.041 Bioorganic & Medicinal Chemistry Letters 14 (2004) 4505–4509