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.

Targeting the hinge glycine flip and the activation loop: novel approach to potent p38α inhibitors.

The p38 MAP kinase is a key player in signaling pathways regulating the biosynthesis of inflammatory cytokines. Small molecule p38 inhibitors suppress the production of these cytokines. Therefore p38 is a promising drug target for novel anti-inflammatory drugs.

Design, synthesis, and biological evaluation of novel disubstituted dibenzosuberones as highly potent and selective inhibitors of p38 mitogen activated protein kinase.

Synthesis, biological testing, structure-activity relationships (SARs), and selectivity of novel disubstituted dibenzosuberone derivatives as p38 MAP kinase inhibitors are described. Hydrophilic moieties were introduced at the 7-, 8-, and 9-position of the 2-phenylamino-dibenzosuberones, improving physicochemical properties as well as potency. Extremely potent inhibitors were obtained, with half-maximal inhibitory concentration (IC(50)) values in the low nM range in a whole blood assay measuring the inhibition of cytokine release.

Skepinone-L is a selective p38 mitogen-activated protein kinase inhibitor.

Until now, a lack of inhibitors with high potency and selectivity in vivo has hampered investigation of the p38 mitogen-activated protein kinase (MAPK) signaling pathway. We describe the design of skepinone-L, which is, to our knowledge, the first ATP-competitive p38 MAPK inhibitor with excellent in vivo efficacy and selectivity. Therefore, skepinone-L is a valuable probe for chemical biology research, and it may foster the development of a unique class of kinase inhibitors.

Modeling and benchmark data set for the inhibition of c-Jun N-terminal kinase-3.

The goal of this paper is to present and describe a novel 2D- and 3D-QSAR (quantitative structure-activity relationship) binary classification data set for the inhibition of c-Jun N-terminal kinase-3 with previously unpublished activities for a diverse set of compounds. JNK3 is an important pharmaceutical target because it is involved in many neurological disorders. Accordingly, the development of JNK3 inhibitors has gained increasing interest.

Biological evaluation and structural determinants of p38α mitogen-activated-protein kinase and c-Jun-N-terminal kinase 3 inhibition by flavonoids.

A series of 42 naturally occurring flavonoids and one flavonoid glucuronide were tested for their ability to inhibit p38α mitogen-activated protein kinase (p38α) and c-Jun-N-terminal kinase 3 (JNK3). Potent inhibitors with IC(50) values in the low micromolar range were identified. Structure-activity relationships were evaluated and the most promising compounds were docked into the ATP binding site of these kinases.

Tri- and tetrasubstituted imidazoles as p38α mitogen-activated protein kinase inhibitors.

The synthesis of 2,4,5-trisubstituted and 1,2,4,5-tetrasubstituted imidazoles as potent p38α mitogen-activated protein kinase inhibitors is described. The trisubstituted imidazole series was found to be more potent than the tetrasubstituted imidazole series. Many of these compounds show low-nanomolar activities in the isolated p38α MAP kinase inhibition assay.

Synthesis and biological testing of N-aminoimidazole-based p38alpha MAP kinase inhibitors.

The p38 mitogen-activated protein (MAP) kinase alpha plays a central role in the regulation of cellular responses such as differentiation, proliferation, apoptosis, and inflammation. Inhibition of p38 results in decreased synthesis of pro-inflammatory cytokines. To date, diverse p38alpha inhibitors are in phase II clinical trials for numerous cytokine-dependent diseases.

Design, synthesis and SAR of phenylamino-substituted 5,11-dihydro-dibenzo[a,d]cyclohepten-10-ones and 11H-dibenzo[b,f]oxepin-10-ones as p38 MAP kinase inhibitors.

The p38 MAP kinase is a key enzyme in inflammatory diseases as it is involved in the biosynthesis of proinflammatory cytokines such as TNF-alpha and IL-1beta. Small molecule p38 inhibitors suppress the production of these cytokines and therefore p38 is a promising drug target for novel anti-inflammatory therapeutics. In this study, we report the design, synthesis, and SAR of novel N-substituted 11H-dibenzo[b,f]oxepin-10-ones and 5,11-dihydro-dibenzo[a,d]cyclohepten-10-ones as p38 inhibitors.

Pyridinylquinoxalines and pyridinylpyridopyrazines as lead compounds for novel p38 alpha mitogen-activated protein kinase inhibitors.

Various substituted 2(3)-(4-fluorophenyl)-3(2)-(pyridin-4-yl)quinoxalines and 2(3)-(4-fluorophenyl)-3(2)-(pyridin-4-yl)pyridopyrazines were synthesized as novel p38 alpha MAP kinase inhibitors via different short synthetic strategies with high variation possibilities. The formation of the quinoxaline/pyridopyrazine core was achieved from alpha-diketones and o-phenylenediamines/alpha-diaminopyridines under microwave irradiation. Introduction of an amino moiety at the pyridine C2 position of the 2(3)-(4-fluorophenyl)-3(2)-(pyridin-4-yl)quinoxalines led to compounds showing potent enzyme inhibition down to the double-digit nanomolar range (6f; IC(50) = 81 nM).

3,4-Diaryl-isoxazoles and -imidazoles as potent dual inhibitors of p38alpha mitogen activated protein kinase and casein kinase 1delta.

In this study, we report on the discovery of isoxazole 1 as a potent dual inhibitor of p38alpha (IC(50) = 0.45 microM) and CK1delta (IC(50) = 0.23 microM).

Role of the hydrogen bonding heteroatom-Lys53 interaction between the p38alpha mitogen-activated protein (MAP) kinase and pyridinyl-substituted 5-membered heterocyclic ring inhibitors.

In the framework of investigating the role of heteroatoms in pyridinyl-substituted 5-membered (hetero)cycles as potential p38alpha MAP kinase inhibitor scaffolds, cyclopentene, pyrrole, furan, and imidazole analogues were synthesized and tested with respect to their ability to inhibit p38alpha MAP kinase. The vicinal pyridine/4-fluorophenyl pharmacophore was conserved, such as in the prototypical imidazole inhibitor SB203580. The strength of the HB interaction was calculated and compared to the biological data.

Implications for selectivity of 3,4-diarylquinolinones as p38alphaMAP kinase inhibitors.

In this study we report on the specificity profiling of the MAP kinase inhibitors 1, 2, and 3 in a panel of 78 protein kinases including the MAPK isoforms p38(alpha,beta,gamma,delta), JNK1/2/3, and ERK1/2/8 showing 3-(4-fluorophenyl)-4-pyridin-4-ylquinolin-2(1H)-one (1) to be highly selective for p38alphaMAPK with an IC(50) of 1.8 microM. In contrast, besides p38alpha the isoxazoles 2 and 3 significantly inhibited JNK2/3 and further kinases beyond the MAPK family such as PKA, PKD, Lck, and CK1.