Novel 2,3-Dihydro-1,4-Benzoxazines as Potent and Orally Bioavailable Inhibitors of Tumor-Driven Angiogenesis

Abstract

Angiogenesis is vital for solid tumor growth, and its prevention is a proven strategy for the treatment of disease states such as cancer. The vascular endothelial growth factor (VEGF) pathway provides several opportunities by which small molecules can act as inhibitors of endothelial proliferation and migration. Critical to these processes is signaling through VEGFR-2 or the kinase insert domain receptor (KDR) upon stimulation by its ligand VEGF. Herein, we report the discovery of 2,3-dihydro-1,4-benzoxazines as inhibitors of intrinsic KDR activity (IC 50 < 0.1 microM) and human umbilical vein endothelial cell (HUVEC) proliferation with IC 50 < 0.1 microM. More specifically, compound 16 was identified as a potent (KDR: < 1 nM and HUVEC: 4 nM) and selective inhibitor that exhibited efficacy in angiogenic in vivo models. In addition, this series of molecules is typically well-absorbed orally, further demonstrating the 2,3-dihydro-1,4-benzoxazine moiety as a promising platform for generating kinase-based antiangiogenic therapeutic agents.

Discovery of a New Series of Naphthamides as Potent VEGFR-2 Kinase Inhibitors

“…It is currently in phase III clinical trials for the treatment of advanced HCC. 18 In 2008, Amgen Inc. researchers reported a series of naphthamides 19 and 2,3-dihydro-1,4-benzoxazines 20 as potent VEGFR inhibitors. Of naphthamides, representative compound 2 (Figure 1) showed IC 50 values of 0.5 and 8 nM for VEGFR-2 and VEGF-induced proliferation of human umbilical vein endothelial cells (HUVEC), respectively.…”

Vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors: development and validation of predictive 3-D QSAR models through extensive ligand- and structure-based approaches

“…Along with the classical cross-validation (CV) techniques (Leave One Out, K-Fold, MonteCarlo and Y-Scrambling), 10 different external test sets were used to estimate the models' predictive capability. A total of 262 published compounds with known activities and unknown binding modes [15][16][17][18][19][45][46][47][48] (Supplementary Material Table SM-1) were collected. As an extension of previously reported applications [39,42,[45][46][47], in order to evaluate the 3-D QSAR model predictive abilities, either ligand-based (LB) or SB molecular alignments were ruled out by means of the programs Surflex-Sim [48], Omega/Rocs [49][50][51][52] and Balloon/ShaEP [53][54][55] for the LB and AutoDock4 [56], AutoDock Vina (herein just Vina), DOCK, Plants, ParaDocks and Surflex-Dock for the SB.…”

“…Extensive design of these small molecule inhibitors has been done by in silico screening and design methodologies. VEGFR-2 is a likely target for computational drug design as small molecule inhibitors have been derived from many molecular scaffolds, including quinazolines [14,15], naphtamides [16], furo [2,3-d]pyrimidines [17], pyridinyltriazines [18], pyrimidinyllindazoles [19], and most recently thieno [3,2-d]pyrimidinones and thieno [1][2][3] triazines [20], offering an expansive data set for design and optimization. Using SciFinder Ò as a representative search tool for the literature, 17 publications were identified which used 3-D QSAR methods to study inhibitors of VEGFR-2 [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37].…”

Molecular Dynamics Simulation of VEGFR2 with Sorafenib and Other Urea-Substituted Aryloxy Compounds

“…The structure of VEGFR2 receptor was taken from Protein Data Bank with the ID code 2RL5 [15] ( Figure 1). The receptor was prepared using Protein Prepare wizard.…”