2-(3-{(3R,4R)-4-Methyl-3-[meth-yl(7H-pyrrolo-[2,3-d]pyrimidin-4-yl)amino]-piperidin-1-yl}oxetan-3-yl)aceto-nitrile monohydrate.

In the title compound, C18H24N6O·H2O, the piperidine ring adopts a chair conformation with an N-C-C-C torsion angle of 39.5 (5)° between the cis-related substituents. The pyrrole N-H group forms a water-mediated inter-molecular hydrogen bond to one of the N atoms of the annelated pyrimidine ring. The water mol-ecule connects two organic mol-ecules and is disorderd over two positions (occupancies of 0.48 and 0.52). The crystal packing shows zigzag chains of alternating organic and water mol-ecules running parallel to the a axis.

2-[5-Bromo-1-(3-chloro-benz-yl)-2-methyl-1H-indol-3-yl]acetic acid.

In the title compound, C18H15BrClNO2, the indole ring system forms a dihedral angle of 86.9 (2)° with the 3-chloro-benzyl ring. In the crystal, mol-ecules form inversion dimers connected via pairs of O-H⋯O hydrogen bonds.

3-(4-Bromo-phen-yl)-1-phenyl-1H-pyrazole-4-carbaldehyde.

The asymmetric unit of the title compound, C16H11BrN2O, contains two independent mol-ecules with slightly different geometries. The 4-bromo-benzene ring forms dihedral angles of 26.0 (2) and 39.9 (7)° with the pyrazole ring in the two mol-ecules while the phenyl ring is oriented at 19.7 (5) and 7.3 (0)° with respect to the pyrazole ring.

6-(4-Meth-oxy-phen-yl)-7-phenyl-2,3-dihydro-1H-pyrrolizine-5-carbaldehyde.

The 4-meth-oxy-phenyl residue in the title compound, C(21)H(19)NO(2), is oriented at a dihedral angle of 54.6 (5)° with respect to the phenyl ring and at a dihedral angle of 52.5 (8)° with respect to the pyrrole ring of the pyrrolizine system. The phenyl ring is oriented at a dihedral angle of 36.2 (5)° with respect to the pyrrole ring. The meth-oxy group makes a C-C-O-C torsion angle of 3.8 (9)° with the attached benzene ring.

6-(4-Chloro-phen-yl)-7-phenyl-2,3-dihydro-1H-pyrrolizine-5-carbaldehyde.

The 4-chloro-phenyl residue in the title compound, C(20)H(16)ClNO, is oriented at a dihedral angle of 53.6 (3)° towards the phenyl ring and 42.0 (9)° towards the pyrrole ring of the pyrrolizine template. The phenyl ring is oriented at a dihedral angle of 45.4 (4)° towards the pyrrole ring.

A p38 substrate-specific MK2-EGFP translocation assay for identification and validation of new p38 inhibitors in living cells: a comprising alternative for acquisition of cellular p38 inhibition data.

The fundamental role of p38 mitogen-activated protein kinases (MAPKs) in inflammation underlines their importance as therapeutic targets for various inflammatory medical conditions, including infectious, vascular, neurobiological and autoimmune disease. Although decades of research have yielded several p38 inhibitors, most clinical trials have failed, due to lack of selectivity and efficacy in vivo. This underlines the continuous need to screen for novel structures and chemotypes of p38 inhibitors. Here we report an optimized MK2-EGFP translocation assay in a semi-automated image based High Content Analysis (HCA) system to screen a combinatorial library of 3362 proprietary compounds with extensive variations of chemotypes. By determining the levels of redistribution of MK2-EGFP upon activation of the Rac/p38 pathway in combination with compound treatment, new candidates were identified, which modulate p38 activity in living cells. Based on integrated analysis of TNFα release from human whole blood, biochemical kinase activity assays and JNK3 selectivity testing, we show that this cell based assay reveals a high overlap and predictability for cellular efficacy, selectivity and potency of tested compounds. As a result we disclose a new comprehensive short-list of subtype inhibitors which are functional in the low nanomolar range and might provide the basis for further lead-optimization. In accordance to previous reports, we demonstrate that the MK2-EGFP translocation assay is a suitable primary screening approach for p38-MAPK drug development and provide an attractive labor- and cost saving alternative to other cell based methods including determination of cytokine release from hPBMCs or whole blood.

Arylpyrrolizines as inhibitors of microsomal prostaglandin E2 synthase-1 (mPGES-1) or as dual inhibitors of mPGES-1 and 5-lipoxygenase (5-LOX).

We synthesized and evaluated inhibitors for the microsomal prostaglandin E2 synthase-1 (mPGES-1), based on the arylpyrrolizine scaffold. In a cell free mPGES-1 assay several "sulfonimides" exceeded our lead ML3000 (3) in potency. The most promising compound, the tolylsulfonimide 11f, revealed an IC50 of 2.1 microM and is equipotent to the literature reference molecule MK886 (1). Selected compounds also potently reduced 5-LOX product formation in intact cells. Inhibition of isolated COX was occasionally remarkably cut down.