P38-MAP kinase

The fact that the aliosterically preferred conformation may be relatively rare in the library of conformations available to the receptor may have kinetic implications. Specifically, if the binding site for the modulator appears only when the preferred conformation is formed spontaneously, then complete conversion to alios terically modified receptor may require a relatively long period of equilibration. For example, the allosteric p38 MAP kinase inhibitor BIRB 796 binds to a conformation of MAP kinase requiring movement of a Phe residue by 10 angstroms (so-called out conformation). The association rate for this modulator is 8.5 x 105 M-1 s-1, 50 times slower than that required for other inhibitors (4.3 x 107 M 1 s-1). The result is that while other inhibitors reach equilibrium within 30 minutes, BIRB 376 requires 2 full hours of equilibration time [8],... 

Poly(ADP-ribose)polyrmerase (PARP) inhibitors, 42 (2004) 125 P2 Purinoreceptor ligands, 38 (2001) 115 p38 MAP kinase inhibitors, 38 (2001) 1 Paclitaxel, anticancer agent, 32 (1995) 289... 

Pearlman, D. A. Charifson, P. S., Are free energy calculations useful in practice A comparison with rapid scoring functions for the p38 MAP kinase protein system, J. Med. Chem. 2001, 44, 3417-3423... 

McKenna, J. M., F. Halley, J. E. Souness, I. M. McLay, S. D. Pickett, A. J. Collis, K. Page, and I. Ahmed. An algorithm-directed two-component library synthesized via solid-phase methodology yielding potent and orally bioavailable p38 MAP kinase inhibitors, J. Med. Chem. 2002, 45, 2173-2184... 

II/III. MAP kinases, especially the classical MAP kinase (ERK1/2) pathway and the p38 MAP kinase a// pathway ... 

Figure 7.1 Major signaling pathways relevant to this chapter. Simplified schematic diagram of the major signaling pathways which impinge on mRNA translation I. The phosphatidylinositide 3-kinase (PI 3-kinase) pathway II/III. MAP kinases, especially the classical MAP kinase (ERK) pathway and the p38 MAP kinase pathway IV. The mammalian target of rapamycin (mTOR) pathway. Strictly, this diagram shows the rapamycin-sensitive events linked to mTORCl. Selected inhibitors and their sites of action are shown. A numberof components and cross-connections have been omitted for clarity.

MK2 (also termed MAP kinase-activated protein kinase 2, MAPKAP-K2) is activated by p38 MAP kinase a// (Kotlyarov et al, 2002 Roux and Blenis, 2004). MK2 plays a key role in the control of the production of certain cytokines, for example, tumor necrosis factor a. MK2 does so by phosphorylating proteins that bind specifically to the regulatory regions in the S untranslated regions (UTRs) of such mRNAs (Hitti et al, 2006). These regions contain AU-rich elements (AREs) to which proteins such as HnRNP A1 also bind. 

To date, no specific inhibitors ofMK2 have been reported. However, since MKT is activated by p38 MAP kinases a// , use of SB203580 will prevent its activation (but also interferes with the control of other kinases, such as Mnkla, that are activated by the same pathway). 

Zhang, H., Shi, X., Hampong, M., Blanis, L., and Pelech, S. (2001). Stress-induced inhibition of ERK1 and ERK2 by direct interaction with p38 MAP kinase. J. Biol. Chem. 276, 6905-6908. 

A process research investigation on p38 MAP kinase inhibitors examined the synthesis (on 7 mol scale) of a group of closely related pyrimidinones such as 37, by condensation of a number of arylacetic esters with 4-cyanopyridine and methyl isothiocyanate. Other nitriles were also examined but were much less successful than 4-cyanopyridine 3-cyanopyridine gave a much lower yield and both benzonitrile and 2-cyanopyridine failed completely <06T11714>. 

Within an SAR study of p38 MAP kinase inhibitors, a series of 3,4-dihydropyrimido[4,5-ri pyrimidin-2-ones and 3,4-dihydropyrido[4,3-rijpyrimidin-2-ones were prepared <06BMCL4400>. 

Nicewonger R, Baldino C, Evans M (2003) The accelerated development of an optimized synthesis of 1,2,4-oxadiazoles. Tetrahedron Lett 44 9337-9341 Ondruschka B, Nuchter M, Bonrath W (2004) Microwave assisted synthesis— a critical technology overview. Green Chem 6 128-141 Regan J, Breitfelder S Cirillo P (2002) Pyrazole urea-based inhibitors of p38 MAP kinase from lead compound to clinical candidate. J Med Chem 45 2994-3008... 

Canesi, L. et al., Signalling pathways involved in the physiological response of mussel hemocytes to bacterial challenge the role of stress-activated p38 MAP kinases, Devel. Compar. Immunol., 26, 325, 2002. 

Physicochemical properties rather than reactivities were also explored. Molecular electrostatic potential (MEP) was calculated for the [l,2,4]triazolo[4,3- ]pyridine fragment 23, according to the CHELPG algorithm. This afforded a prediction of its H-bond acceptor ability in view of the synthesis of p38 MAP kinase inhibitors <2005JME5728>. Tautomerism was also examined for compound 24, also postulated as two possible acyclic structures. The ab initio self-consistent field (SCF)-calculated energies support 24a as the most stable tautomer <1999MRC493>. 

An example of the use of NMR to design inhibitors of the protein kinase p38 is shown below. The first NMR spectrum shows the resonance peaks of nicotinic acid (a) and 2-phenoxy benzoic acid (b) in the absence of a target enzyme. When a target enzyme is added, in this case the p38 MAP kinase, binding of the ligand and the enzyme causes line broadening and attenuation of the resonance peaks. This is shown by the second NMR spectrum, in which the affected peaks are those of the 2-phenoxy benzoic acid (from 7.2 ppm to 6.6 ppm), indicating the interactions between p38 MAP kinase and 2-phenoxy benzoic acid. 

Fig. 14.11 Selected examples for lead optimization under consideration of multiple parameters simultaneously (A) thrombin inhibitors, (B) p38 MAP kinase inhibitors, (C) MMP-8 inhibitors.

Fig. 12.6 H/D-Ex results of p38 MAP kinase at pH 7.0 at 25 °C with or without SB203580 [56], Each block represents a pepsingenerated peptide. Each block has six time points and the level of deuterium incorporation is indicated by colors that vary according to the legend at the bottom right. Upper and middle blocks show the results without and with SB203580, respectively.

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