249936-55-8Relevant academic research and scientific papers
The effect of RO3201195 and a pyrazolyl ketone P38 MAPK inhibitor library on the proliferation of Werner syndrome cells
Bagley, Mark C.,Dwyer, Jessica E.,Baashen, Mohammed,Dix, Matthew C.,Murziani, Paola G. S.,Rokicki, Michal J.,Kipling, David,Davis, Terence
, p. 947 - 956 (2016/01/15)
Microwave-assisted synthesis of the pyrazolyl ketone p38 MAPK inhibitor RO3201195 in 7 steps and 15% overall yield, and the comparison of its effect upon the proliferation of Werner Syndrome cells with a library of pyrazolyl ketones, strengthens the evidence that p38 MAPK inhibition plays a critical role in modulating premature cellular senescence in this progeroid syndrome and the reversal of accelerated ageing observed in vitro on treatment with SB203580.
Microwave-assisted synthesis of 5-aminopyrazol-4-yl ketones and the p38MAPK inhibitor RO3201195 for study in Werner syndrome cells
Bagley, Mark C.,Davis, Terence,Dix, Matthew C.,Murziani, Paola G.S.,Rokicki, Michal J.,Kipling, David
scheme or table, p. 3745 - 3748 (2009/04/04)
5-Aminopyrazol-4-yl ketones are prepared rapidly and efficiently using microwave dielectric heating from β-ketonitriles by treatment with N,N′-diphenylformamidine followed by heterocyclocondensation by irradiation with a hydrazine. The inhibitory activity of RO3201195 prepared by this methodology was confirmed in hTERT-immortalized HCA2 and WS dermal fibroblasts at 200 nM concentration, both by ELISA and immunoblot assay, and displays excellent kinase selectivity for p38α MAPK over the related stress-activated kinase JNK.
Discovery of S-[5-amino-1-(4-fluorophenyl)-1H-pyrazol-4-yl]-[3-(2,3- dihydroxypropoxy)phenyl]-methanone (RO3201195), an orally bioavailable and highly selective inhibitor of p38 Map kinase
Goldstein, David M.,Alfredson, Tom,Bertrand, Jay,Browner, Michelle F.,Clifford, Ken,Dalrymple, Stacie A.,Dunn, James,Freire-Moar, Jose,Harris, Seth,Labadie, Sharada S.,La Fargue, JoAnn,Lapierre, Jean Marc,Larrabee, Susan,Li, Fujun,Papp, Eva,McWeeney, Daniel,Ramesha, Chakk,Roberts, Rick,Rotstein, David,San Pablo, Bong,Sjogren, Eric B.,So, On-Yee,Talamas, Francisco X.,Tao, Will,Trejo, Alejandra,Villasenor, Armando,Welch, Mary,Welch, Teresa,Weller, Paul,Whiteley, Phyllis E.,Young, Kelly,Zipfel, Sheila
, p. 1562 - 1575 (2007/10/03)
A novel class of highly selective inhibitors of p38 MAP kinase was discovered from high throughput screening. The synthesis and optimization of a series of 5-amino-N-phenyl-1H-pyrazol-4-yl-3-phenylmethanones is described. An X-ray crystal structure of this series bound in the ATP binding pocket of unphosphorylated p38a established the presence of a unique hydrogen bond between the exocyclic amine of the inhibitor and threonine 106 which likely contributes to the selectivity for p38. The crystallographic information was used to optimize the potency and physicochemical properties of the series. The incorporation of the 2,3-dihydroxypropoxy moiety on the pyrazole scaffold resulted in a compound with excellent drug-like properties including high oral bioavailability. These efforts identified 63 (RO3201195) as an orally bioavailable and highly selective inhibitor of p38 which was selected for advancement into Phase I clinical trials.
