Treatment mitogen-activated protein kinase inhibitors

Another important family of kinases for drug discovery is the mitogen-activated protein kinases (MAPKs). These are proline-directed serine/threonine kinases that activate their substrates by dual-phosphorylation. MAPK enzymes are activated by a variety of signals including growth factors and cytokines, discussed in chapter 6. The MAPK family plays a critical role in cell cycle progression. Small molecule inhibitors of MAPK may have utility in the treatment of cancer. 

As mentioned above, l-DOPA treatment of PD often causes debilitating involuntary movements, termed L-DOPA-induced dyskinesia which in rodent is called as abnormal involuntary movements (AIMs). AIMs involve the activation of the Ras extracellular signal-regulated kinase 1/2 (ERKl/2) mitogen-activated protein kinase signaling pathway. Lovastatin, a specific inhibitor of HMG-CoA reductase, prevents Ras isoprenylation activity and subsequently phosphorylation of ERKl/2 (pERKl/2) (Schuster et al., 2008). It is suggested that lovastatin treatment before l-DOPA exposure reduces AIM incidence and severity of PD in the 6-hydroxydopamine (6-OHDA) rat model suggesting that lovastatin may represent... 

Whittaker SR, Walton MI, Garrett MD et al. (2004) The cyclin-dependent kinase inhibitor CYC202 (R-roscovitine) inhibits retinoblastoma protein phosphorylation, causes loss of Cyclin Dl, and activates the mitogen-activated protein kinase pathway. Cancer Res 64 262-272 Wijermans PW, Lubbert M, Verhoef G et al. (2005) An epigenetic approach to the treatment of advanced MDS the experience with the DNA demethylating agent 5-aza-2 -deoxycytidine (decitabine) in 177 patients. Ann Hematol 84 (Suppl 1) 9-17... 

Manley PW, et al. Advances in the structural biology, desigu aud cliuical development of VEGF-R kinase inhibitors for the treatment of angiogenesis. Biochim. Biophys. Acta 2004 1697 17-27. Vogtherr M, et al. NMR backbone assignment of the mitogen-activated protein (MAP) kinase p38. J. Biomol. NMR 2005 32 175. 

The cascade of apoptosis may be promoted by mitogen activated protein (MAP) kinase activation. CEP1347, a small molecule MAP kinase inhibitor that crosses the blood brain barrier is protective in MPTP-treated mice (Saporito et al., 1999). A clinical trial showed good tolerability, no interference with L-dopa pharmacokinetics, and no symptomatic effects of treatment over a 4-week period (Parkinson Study Group, 2004). A larger phase II trial has commenced. 

The pyridinylimidazoles are representative of a class of polysubstituted imidazoles which are potent inhibitors of p38 Mitogen-Activated Protein (MAP) kinase.(i, 2) (Figure 1) These con5)ounds have been indicated for the treatment of inflammatory diseases due to their mode of action which involves upstream regulation of several pro-inflammatory cytokines such as IL-1 (interleukin-1) and TNF (tumor necrosis factor).(J) Effective syntheses for this class of compounds have been described. 5)... 

---