Roland Selig

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.

Fluorescence polarization binding assay to develop inhibitors of inactive p38α mitogen-activated protein kinase

Development of inhibitors that target inactive kinase conformations is becoming a more attractive approach to kinase inhibitor research. The major advantage of this methodology is that targeting the inactive conformation reduces competition with high intracellular adenosine triphosphate (ATP) concentrations. p38alpha Mitogen-activated protein kinase (MAPK) signaling has been identified as the principal mediator of inflammation associated with a spectrum of disorders (e.g., arthritis, Alzheimers disease, various malignancies). To allow identification and development of p38alpha MAPK inhibitors that preferentially bind to the inactive conformation, a novel fluorescence polarization-based binding assay is presented. The assay is homogeneous, requires low amounts of the kinase and fluoroprobe, and does not rely on radioactivity. It may, therefore, offer an inexpensive alternative to current p38alpha MAPK inhibitor screening methods. The validation of the system with known p38alpha MAPK inhibitors confirmed that the binding assay, rather than the conventional enzyme activity assay, correlates with cellular efficacy. Finally, we show that pyridinyl imidazoles that potently bind to the inactive p38alpha MAPK prevent activation of p38 MAPK in living cells, suggesting that pyridinyl imidazoles other than SB203580 are able to induce the DFG-out conformation that is incompatible with activation (where DFG is a single-letter amino acid code for the aspartate-phenylalanine-glycine sequence at the start of the activation loop).

A Frozen Analogue Approach to Aminopyridinylimidazoles Leading to Novel and Promising p38 MAP Kinase Inhibitors

In this study we report the design, synthesis, and biological evaluation of constrained aminopyridinylimidazoles as p38α MAP kinase inhibitors. The frozen analogue approach focused on the pyridinyl unit, using purine bioisosteres as constrained structure analogues. The identification of the most potent bioisostere was followed by a further derivatization to address hydrophobic region II. In combination with C-2 modifications of the imidazole core, we were able to design highly active inhibitors on the p38α MAP kinase. The inhibitor design presented herein represents a promising and highly efficient advancement of recent stages of development in this class of p38 MAP kinase inhibitors. In combination with the highly flexible synthetic strategy, directions toward further investigations of complex C-5 modifications of diarylimidazoles are indicated.

Conformational effects on potency of thioimidazoles and dihydrothiazolines

We investigated the effect of steric restriction and hindrance on inhibitors directed against the biological activity of p38α MAP kinase. The structural reduction of the early lead compound SKF86002 into three structural classes of optimized SKF86002-like inhibitors produced a strong effect on inhibitory potency. This effect was investigated by conformational analysis and docking experiments.

2-(4-Fluoro-phen-yl)-N-{4-[6-(4-fluoro-phen-yl)-2,3-dihydro-imidazo[2,1-b][1,3]thia-zol-5-yl]pyridin-2-yl}acetamide.

In the crystal structure of the title compound, C24H18F2N4OS, the imidazole system makes dihedral angles of 34.3 (1) and 43.9 (1)°, respectively, with the directly attached 4-fluorophenyl and pyridine rings. The crystal structure is stabilized by intermolecular N—H⋯N hydrogen bonding and by an intramolecular C—H⋯O hydrogen interaction. The F atom of the 2-(4-fluorophenyl) group is disordered over two positions with site-occupancy factors of 0.75 and 0.25.

4-Chloro-1-(4-methyl­phenyl­sulfon­yl)-1H-pyrrolo[2,3-b]pyridine

The crystal structure of the title compound, C14H11ClN2O2S, features a three-dimensional network stabilized by π–π interactions between the rings of the 4-methylphenylsulfonyl protecting group [centroid–centroid distance = 3.623 (1) Å]. The 4-methylphenylsulfonyl ring makes a dihedral angle of 79.60 (6)° with the 4-chloro-1H-pyrrolo[2,3-b]pyridine unit.

(2Z)-2-Fluoro-N-{4-[5-(4-fluoro­phen­yl)-2-methyl­sulfanyl-1H-imidazol-4-yl]-2-pyrid­yl}-3-phenyl­acrylamide

The asymmetric unit of the title compound, C24H18F2N4OS, contains two crystallographically independent molecules, A and B, which are linked into two chains of A and B molecules by intermolecular N—H⋯O hydrogen bonds. The three-dimensional network is stabilized by π–π interactions between the pyridine rings and phenyl rings of different residues, with centroid–centroid distances of 3.793 (1) and 3.666 (2) Å. The molecular conformation is stabilized by intramolecular N—H⋯F hydrogen bonds (2.15/2.15Å). The imidazole rings make dihedral angles of 39.5 (2)/38.5 (2) and 31.8 (2)/33.2 (2)° with the 4-fluorophenyl rings and the pyridine rings, respectively. The methyl group of molecule A is disorderd in a 0.60:0.40 ratio.

7-[4-(4-Fluoro-phen-yl)-2-methyl-sulfanyl-1H-imidazol-5-yl]tetra-zolo[1,5-a]pyridine.

The crystal structure of the title compound, C15H11FN6S, forms a three-dimensional network stabilized by π–π interactions between the imidazole core and the tetrazole ring of the tetrazolopyridineunit; the centroid–centroid distance is 3.627 (1) Å. The crystal structure also displays bifurcated N—H⋯(N,N) hydrogen bonding and C—H⋯F interactions. The former involve the NH H atom of the imidazole core and the tetrazolopyridine N atoms, while the latter involve a methyl H atom, of the methylsulfanyl group, and the 4-fluorophenyl F atom. In the molecule, the imidazole ring makes dihedral angles of 40.45 (9) and 17.09 (8)°, respectively, with the 4-fluorophenyl ring and the tetrazolopyridine ring mean plane.

2-(Bicyclo­[2.2.1]hept-5-en-2-yl)-1H-pyrrolo­[2,3-b]pyridine

The crystal structure of the title compound, C14H14N2, displays intermolecular N—H⋯N hydrogen bonds, forming dimers of enantiomeric molecules via a crystallographic centre of inversion.

4-Chloro-7-methoxy-methyl-2-phenyl-7H-pyrrolo[2,3-b]pyridine.

In the title compound, C15H13ClN2O, the phenyl group makes a dihedral angle of 7.91 (8)° with the pyrrole ring. The crystal structure forms a three-dimensional network stabilized by π–π interactions [centroid–centroid distances = 3.807 (1) Å] between the pyridine and phenyl rings and via intermolecular C—H⋯O hydrogen bonds.