4058
D. Choquette et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4054–4058
6. See Supplemental material for experimental details regarding the
Supplementary data
regioselective oxidation of 6 and 7.
7. Cellular potency was evaluated by determining the inhibition of human
umbilical vein endothelial cell (HUVEC) proliferation induced by vascular
endothelial growth factor (VEGF). In addition, the HUVEC proliferation assay
was used to assess selectivity at the cellular level comparing on-target
inhibition of VEGF driven proliferation and off-target fibroblast growth factor
(FGF) driven proliferation. Although both growth factors, VEGF and FGF,
Supplementary data associated with this article can be found, in
References and notes
induce HUVEC proliferation, each operates through
pathway. For a detailed description of the KDR enzyme and cellular assays,
see Ref. 3.
a different signaling
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10. Intrinsic clearance values were determined using 0.25 mg microsomal protein/
mL, 1 mM NADPH, and 1 lM test compound in 50 mM potassium phosphate
buffer. Samples were collected at 0, 10, 20, 30, and 40 min. Intrinsic clearance
was determined from the half-life.
11. Liver microsomal (HLM, RLM) incubations were conducted using 1 mg/mL
4. A Symyx solubility system (Santa Clara, CA) was used for this measurement.
The solubility media were fasted state simulated intestinal fluid (SIF), pH 6.8,
containing 5 mM sodium taurochol, 1.5 mM lecithin, 2.9 mM KH2PO4, and
0.22 M KCl.
5. See Supplemental material for experimental details regarding the preparation
of 4-chloromethyl-6,7-dimethoxyquinoline 15.
protein, 10
(1 mM).
lM of test compound at 37 °C for 60 min, with or without NADPH
12. Compound 27 exhibits >100ꢀ selectivity against the following kinases:
Aurora 1, Aurora 2, BTK, c-Met, JAK3, and PI3Kd. In addition,
compound 27 demonstrates >10ꢀ selectivity against c-FMS, TIE2, and
LCK.