P38 inhibitors

A number of distinct chemotypes have been reported as JNK inhibitors. In addition, a significant number of p38 inhibitors have also been found to have JNK inhibitory activity. This review will primarily focus on specific JNK inhibitors which have little or no p38 activity. 

The enantiomers of 15, with structural similarity to the imidazole-based p38 inhibitors, have been reported to be potent inhibitors of JNK3 (ICso 3 nM) and p38 (TCso SO nM) with significant neuroprotective effects in cells [53]. 

Tan pathology Apoptosis Neurotransmission deficits APP production inhibitors A 3-Selective regulators Phosphatase activators GSK-3 inhibitors Cdk5 inhibitors P38 inhibitors JNK inhibitors Caspase inhibitors Neurotrophic agents Phenserine tartrate Posiphen Reticulons Chaperones/SLF-CR Axonyx Axonyx/National Institutes of Health Howard Hughes Medical Institute... 

Complement activation inhibitors P38 inhibitors Caspase-1 inhibitors eNOS inhibitors Argisat eNOS Pharmaceuticals... 

It is possible to perform regiospecific benzylic radical bromination of 3,4-dihydro-12/-[l,6]naphthyridin-2-ones, followed by spontaneous elimination, to form quinolinones (Scheme 10). The products were used as part of a programme aimed at novel p38 inhibitors <2003BML467>. 

Pyrazole derivatives, (VII), prepared by Allen (7), were effective as p38 inhibitors and used in treating rheumatoid arthritis. 

Finally, ASKA mice should provide crucial information regarding the therapeutic index. ASKA-based in-vivo studies will be able to establish mechanism and target-based efficacy and toxicity for most protein kinases. Such information should prove useful in the preclinical testing of development candidates, because it will allow distinction between mechanism (target)-based and compound (off-target)-based toxicities [35], At this point, we would like to challenge the scientific community and express our interest in the development of p38-ASKA mice, to either promote or discourage the numerous clinical trials of p38 for various indications and to clarify the associated liver toxicity upon treatment of patients with p38 inhibitors. 

Identification of several new protein kinase targets of the p38 inhibitor SB203580... 

For example, compounds from the pyridinylimidazole class of p38 inhibitors have served as leads for c-Raf [123] and AlkS [124]. For further details on the role of computational chemistry in kinase inhibitor structure-based design strategies and the range of computational tools being applied in this area see a recent overview by Woolfrey and Weston [89]. 

X-ray crystallography is a powerful and direct tool to understand kinase inhibitory mechanisms. Key experiments demonstrate that inhibitors interact with multiple regions of kinases that lead to mechanisms that may or may not be competitive with substrates. As examples, p38 inhibitors fall into both groups. 

Davidson W, Frego L, Peet GW, Kroe RR, Labadia ME, Lukas SM, Snow RJ, Jakes S, Grygon CA, Pargellis C, and Werneburg BG. Discovery and Characterization of a Substrate Selective p38 Inhibitor. Biochemistry 2004 43 11658-11671. 

Lee, M. R. Dominguez C.MAP kinase p38 inhibitors clinical results and an intimate look at their interactions with p38alpha protein. Curr. Med. Chem. 2005, 72, 2979-2994. 

Fig. 10. Chemical structures of kinase inhibitors, (a) p38 inhibitor SB203580 (4-[5-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-3H-imidazol-4-yl]pyridine). (b) EGFR inhibitor (N-(3-(6-(3-(trifluoromethyl) phenylamino) pyrimidin-4-ylamino) phenyl) cydopropanecarboxamide). The dashed line indicates hydrogen-bonding interactions with the hinge.

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