Design, synthesis and characterization of N9/N7-substituted 6-aminopurines as VEGF-R and EGF-R inhibitors.

In this study we report on the design, synthesis and biological characterization of novel N(9) or N(7) arylethanone-substituted 6-aminopurines and 6-methoxypurines, respectively, as EGF-R and VEGF-R inhibitors. The compounds were initially profiled in a panel of 24 cancer-relevant protein kinases. Dependent on the regio-substitution of the purine core we found inhibition activity for EGF-R and VEGF-R with IC(50) values in the microM range. The two novel N(9)/N(7) 2-(6-amino-purine)-1-(1H-indole-3-yl)ethanone derivatives were characterized in an enhanced panel of 78 kinases showing the N(9) derivative to also inhibit MNK1 and IRR while the N(7) isomer was found to be specific for VEGF-R2.

Design, synthesis, and biological evaluation of novel 3-aryl-4-(1H-indole-3yl)-1,5-dihydro-2H-pyrrole-2-ones as vascular endothelial growth factor receptor (VEGF-R) inhibitors.

In this study we report on the design, synthesis, and biological evaluation of pyrrole-2-one 2 to be a highly potent VEGF-R2/3 inhibitor with IC 50 of 31/37 nM. The novel 3,4-diaryl-2 H-pyrrole-2-ones were designed on the basis of the modeled binding mode of the corresponding 1 H-pyrrole-2,5-dione (maleimide) VEGF-R2/3 inhibitor 1 indicating two H-bond ligand-protein interactions in the ATP pocket for the amide 2 but not for the isomer 3. Flexible synthetic routes to 3,4-diaryl-2 H-pyrrole-2-ones and structure-activity relationships for the compounds in a panel of 24 therapeutically relevant protein kinases (IC 50 values) are presented. Accordingly to the in vitro data, compounds 1 and 2 were found to possess highly potent antiangiogenic activities in the cellular HLMEC sprouting assay and also slightly induced apoptosis in HDMECs whereas 3 was determined to be significantly less active. Hence, the pyrrole-2-one moiety was dissected from the corresponding maleimide protein kinase inhibitor as a suitable key pharmacophore.

Design, synthesis, and biological evaluation of novel Tri- and tetrasubstituted imidazoles as highly potent and specific ATP-mimetic inhibitors of p38 MAP kinase: focus on optimized interactions with the enzyme's surface-exposed front region.

The synthesis, biological testing, and SAR of novel 2,4,5- and 1,2,4,5-substituted 2-thioimidazoles are described. Amino, oxy, or thioxy substituents at the 2-position of the pyridinyl moiety were evaluated for their contributions to inhibitor potency and selectivity against p38 mitogen activated protein kinase (p38 MAPK) as well as for the ability to minimize cytochrome P450 (CYP450) inhibition. Incorporation of polar substituted (cyclo)aliphatic amino substituents (e.g., tetrahydropyranylamino), which positively interacted with the surface-exposed front region (hydrophobic region II) of the enzyme led to the identification of extremely potent p38 MAPK inhibitors with p38 IC 50 values in the low nanomolar range. Approximately 90 pyridinylimidazole-based compounds with a range of potencies against p38alpha MAP kinase were further investigated for their ability to inhibit the release of tumor necrosis factor-alpha (TNFalpha) and/or interleukin-1beta (IL-1beta) from human whole blood. Some of the most promising drug candidates underwent selectivity profiling against a panel of 17 different kinases besides p38alpha and/or were tested for their interaction potential toward a number of metabolically relevant CYP450 isozymes.

From five- to six-membered rings: 3,4-diarylquinolinone as lead for novel p38MAP kinase inhibitors.

In this study we describe the design, synthesis, and biological evaluation of 3-(4-fluorophenyl)-4-pyridin-4-ylquinoline-2(1H)-one (5) as a new inhibitor of MAPK with a p38alphaMAPK IC50 of 1.8 muM. By keeping the common vicinal pyridine/4-F-phenyl pharmacophore, such as in prototypical imidazole 20 or isoxazole 13 but in 5 connected to the six-membered quinoline core, we were particularly interested in comparing biological activity, details of molecular geometry, and different binding modes of these compounds. Compounds 20 and 13 were active both in the p38alpha- and JNK3-assay, whereas 5 was selective for p38alpha, with no JNK3 inhibition. By comparing the X-ray structures of the compounds, we found a significantly larger distance between the pyridine and the 4-F-phenyl moiety in five-membered core structures relevant for ligand-protein interactions. Molecular modeling studies support the results based on differences in the ATP pockets of p38alpha and JNK3. Because most five-membered core based p38alpha inhibitors show also activity for JNK3, compound 5 is an interesting lead for selective p38alpha inhibitors.