%0 Journal Article
%T Identification of a Novel Series of Potent TrkA Receptor Tyrosine Kinase Inhibitors
%A St¨¦phane L. Raeppel
%A Fr¨¦d¨¦ric Gaudette
%A Hannah Nguyen
%A Normand Beaulieu
%A James Wang
%A Christiane Maroun
%A Jeffrey M. Besterman
%A Arkadii Vaisburg
%J International Journal of Medicinal Chemistry
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/412614
%X A novel series of N-(3-(6-substituted-aminopyridin-3-yloxy)phenyl)-2-oxo-3-phenylimidazolidine-1-carboxamides targeting TrkA receptor tyrosine kinase was identified. SAR study of the series allowed us to design and synthesize compounds possessing inhibitory activity of TrkA kinase enzyme in the low nanomolar range with low residual activity against c-Met and with no significant activity against VEGFR2. Tropomyosin-related kinases (Trks) are receptor tyrosine kinases normally expressed in neuronal tissue where they play important role in both development and function of the nervous system [1]. The Trk receptor family is composed of three members (A, B, and C) activated by specific ligands called neurotrophins (NT). Each Trk receptor contains an extracellular domain (ligand binding), a transmembrane region, and an intracellular domain (including kinase domain) which upon binding of their respective ligand (nerve growth factor (NGF) for TrkA, brain-derived growth factor (BDNF) and NT-4/5 for TrkB, and NT3 for TrkC) triggers oligomerization of the receptors, phosphorylation of specific tyrosine residues in the kinase domain, and downstream signal transduction pathways, including survival, proliferation, and differentiation in normal and neoplastic neuronal cells [2¨C4]. While Trks are expressed at low levels outside the nervous system in the adult, deregulation of TrkA and TrkB and their cognate ligands has been described in numerous types of cancers including prostate, breast, colorectal, ovarian, lung, pancreas, melanoma, thyroid, and neuroblastoma and occurs mainly through wild type receptor overexpression, activation, amplification, and/or mutation [5, 6]. Importantly, increased Trks activation in tumor tissues correlates with an aggressive phenotype and poor clinical outcome [6]. There are a limited number of reported selective TrkA receptor tyrosine kinase inhibitors in the literature (Figure 1) [7¨C9]. Developed by Cephalon (now a group member of Teva Pharmaceutical Industries Ltd.), lestaurtinib (CEP-701) is a potent multitargeted tyrosine kinases inhibitor targeting mainly TrkA, Flt3, and JAK2 and is in clinical trials for the treatment of myeloproliferative disorders [10, 11]. More recently, Cephalon disclosed indenopyrrolocarbazole 12a as a potent and selective TrkA inhibitor displaying antitumor properties [12]. Moreover, organoruthenium-pyridocarbazole from Pagano et al. [13], oxindole 3 from GSK [14], isothiazole 5n from Pfizer [15], thiazole 20h from BMS [16], and AZ-23 from AstraZeneca were reported as potent and selective TrkA inhibitors as
%U http://www.hindawi.com/journals/ijmc/2012/412614/