Evaluation of a Series of Naphthamides as Potent, Orally Active Vascular Endothelial Growth Factor Receptor-2 Tyrosine Kinase Inhibitors

Abstract

We have previously shown N-arylnaphthamides can be potent inhibitors of vascular endothelial growth factor receptors (VEGFRs). N-Alkyl and N-unsubstituted naphthamides were prepared and found to yield nanomolar inhibitors of VEGFR-2 (KDR) with an improved selectivity profile against a panel of tyrosine and serine/threonine kinases. The inhibitory activity of this series was retained at the cellular level. Naphthamides 3, 20, and 22 exhibited good pharmacokinetics following oral dosing and showed potent inhibition of VEGF-induced angiogenesis in the rat corneal model. Once-daily oral administration of 22 for 14 days led to 85% inhibition of established HT29 colon cancer and Calu-6 lung cancer xenografts at doses of 10 and 20 mg/kg, respectively.

Recent Advances in Antiangiogenic Agents with VEGFR as Target

“…Weiss and coworkers prepared another series of naphthamides as potent and selective inhibitors of VEGFR-2 [31]. Three of them (26, 27, 28) exhibited good pharmacokinetics following oral dosing and showed potent inhibition of VEGF-induced angiogenesis in the rat cornea.…”

Molecular modeling studies of vascular endothelial growth factor receptor tyrosine kinase inhibitors using QSAR and docking

“…A dataset of 82 compounds, which covered nearly four log units (pIC 50 = 5.8-9.7) for their inhibitory activity, was taken from the published KDR inhibitors [33][34][35]. The structures and their inhibitory activities are listed in Table 1.…”

“…Up to now, there are still a lot of researches focusing on the development of novel inhibitors of KDR [25][26][27][28][29][30][31][32]. Recently, a novel series of KDR inhibitors which can selectively inhibit KDR with high inhibitory activities reported by Harmange et al [33][34][35].…”

“…In the present work, molecular modeling studies of these novel VEGFR-2 (KDR) inhibitors [33][34][35] were performed using 3D-QSAR and docking approach. Three-dimensional quantitative structureactivity relationship (3D-QSAR) methods, such as comparative molecular field analyses (CoMFA) [36,37] and comparative molecular similarity indices analyses (CoMSIA) [38], were applied to these inhibitors to gain insights into how steric, electrostatic, hydrophobic, and hydrogen-bonding interactions influence their activities.…”

Novel VEGFR-2 kinase inhibitors identified by the back-to-front approach

“…After that, types of atoms were assigned and grid representation of 3EWHOK was prepared (AutoGrid4 25 ). 3EWHOK template was validated by docking (AutoDock 4.2, TSRI) 25 with the six active inhibitors: K11, AAX, GIG, LIF, 887 and 900 from PDB ID: 3EWH 1 , 1Y6B 26 , 2OH4 27 , 1YWN 28 , 3B8R 2 and 3B8Q 2 , respectively and all docked poses showed the same configuration as those in the corresponding crystal structures with RMSD less than 2 Å. These results indicated that 3EWHOK was a good VEGFR-2 model for in silico experiment.…”