geoscience.net logo
+ Resolve Article
+ Follow Us
Follow on FacebookFollow on Facebook
Follow on TwitterFollow on Twitter

+ Translate
+ Subscribe to Site Feed
GeoScience Most Shared ContentMost Shared Content

Discovery of a Potent Dihydrooxadiazole Series of Non-ATP-Competitive MK2 (MAPKAPK2) Inhibitors


, : Discovery of a Potent Dihydrooxadiazole Series of Non-ATP-Competitive MK2 (MAPKAPK2) Inhibitors. Acs Medicinal Chemistry Letters 3(2): 100-105

Inhibition of MK2 has been shown to offer advantages over that of p38 MAPK in the development of cures for inflammatory diseases such as arthritis. P38 MAPK knockout in mice was lethal, whereas MK2-null mice demonstrated strong inhibition of disease progression in collagen-induced arthritis and appeared normal and viable. However, it is challenging to develop ATP-competitive MK2 inhibitors due to high ATP binding affinity to the kinase. Non-ATP-competitive MK2 inhibitors interact and bind to the kinase in a mode independent of ATP concentration, which could provide better selectivity and cellular potency. Therefore, it is desirable to identify non-ATP-competitive MK2 inhibitors. Through structure optimization of lead compound 1, a novel series of dihydrooxadiazoles was discovered. Additional structure-activity relationship (SAR) study of this series led to the identification of compound 38 as a non-ATP-competitive MK2 inhibitor with potent enzymatic activity and good cellular potency. The SAR, synthesis, and biological data of dihydrooxadiazole series are discussed.

US$19.90

PMID: 24900435

DOI: 10.1021/ml200238g


Other references

Roopa, N.; Ramesh, B., D.; Das-Gupta, D.K., 2006: Effect of various packaging materials on the shelf-stability of banana chips. Stability of banana (cv 'Nendran') chips packed in polyethylene (PE), polypropylene (PP), paper-aluminium foil-polyethylene laminate (PFP), PP/Nylon/PP and metallised polyester (MP) and stored at 5 degrees C, ambient (19-33 degrees C) an...

Kudryavtsev Y.K.; Semina V.A.; Polov V.S.; Marayeva R.N., 1971: Secondary quartzites of the Kounrad region and their connection with intrusions and copper-molybdenum mineralization. Izvestiya Vysshikh Uchebnykh Zavedeniy Geologiya i Razvedka

Willcox, Louisa., 1999: Bear necessities Grizzlies, wilderness, and the science of extinction. Wild Earth. 1998- Winter; 84: 14-18

Cho, W-Sang.; Kang, H-Seung.; Kim, J.Wook.; Kee Park, C.; Kim, J.Eun., 2011: Cavernous malformation of the cisternal trigeminal nerve. Intradural extraaxial cavernous malformations (CM) are very rare. We report a case of CM originating from the cisternal portion of trigeminal nerve in a 20-year old male. Surgery produced favourable outcome in this case.

Gibson, L.E., 1978: The political implications of the health planning process. Texas Medicine 74(4): 155-156

Tutchenko, N.I.; Semeniutin, I.P.; Kurilets, I.P.; Malinin, V.V.; Ostrenko, A.B., 1986: Combined treatment of patients with duodenogastric reflux. Vrachebnoe Delo: 61-64

Guo, L.; Zhang, D.; Wang, Y.; Malmberg, R.L.; McEachern, M.; Cai, L., 2011: TRFolder: computational prediction of novel telomerase RNA structures in yeast genomes. The identification of Telomerase RNAs (TRs) has been difficult owing to their rapid evolutionary divergence. The common core structure found in all known TRs contains a pseudoknot and a triple helix, which are beyond the capability of existing RNA...

Carvalho Lopes, S.G.doy Bueno.; Schaeffer-Novelli, Y., 1992: Bivalves e gastropodes do Saco da Ribeira, Ubatuba-Sao Paulo 2 Avaliacao das alteracoes ocorridas na taxocenose dos bivalves da Praia do Saco da Ribeira. Boletim de Zoologia. 1989( ); 13: 51-75

Pfisterer, M., 1995: Coronary angioplasty versus aortocoronary bypass surgery in older patients. Role of coronary angioplasty. In elderly patients, who need to be treated increasingly for coronary artery disease, medical therapy is more difficult and the risks of coronary artery bypass graft surgery are markedly increased. PTCA is an alternative treatment with the aim of...

Friedman S.A.; Remold O'donnell E.; Piessens W.F., 1979: Enhanced prostaglandin e production by macrophage activating factor treated peritoneal exudate macrophages. Guinea pig peritoneal macrophages were activated in vitro by culturing with MAF (macrophage activating factor)-containing fractions from stimulated lymphocytes. These macrophage preparations demonstrate a 60% increase in the production of prostagl...