249936-65-0Relevant academic research and scientific papers
2-(HETERO-)ARYL,4-CARBONYL SUBSTITUTED PYRAZOLE DERIVATIVES AS INHIBITORS OF P38 MITOGEN-ACTIVATED PROTEIN KINASE
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Page/Page column 39, (2008/12/05)
Compounds of formula (I) are inhibitors of p38 MAP kinase activity, and are useful in the treatment of, inter alia, inflammatory and autoimmune disease wherein Ring A is aryl, heteroaryl or heterocyclyl of 5-13 atoms; Ring B is optionally substituted aryl or heteroaryl of 5-13 atoms; Z is (a) a radical of formula -(CH2)z-X1-L1-Y- NHCHR1R2 or (b) a radical of formula -(CH2)z-Y1-L1-R wherein R1R2CHNH- and R are respectively N- and C-linked amino acid or amino acid ester groups as defined in the description, and -Y-L1-X1-(CH2)z- and -L1-Y1-(CH2)z- are linker radicals as defined in the description; R7 is hydrogen or -C(=O)R' where R' is hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl or (C1-C6)haloalkyl; R8 is hydrogen or (C1C6)alkyl; R9 is hydrogen, halogen, hydroxyl, (C1-C6)alkoxy, (C1-C6)alkyl; R18 is hydrogen, halogen, hydroxyl, (C1C6)alkoxy (C1-C6)alkyl, - NRaRb where Ra and Rb are hydrogen or (C1-C6)alkyl, or optionally substituted aryl, heteroaryl or heterocyclyl or Ra and Rb when taken together with the nitrogen to which they are attached form a cyclic amino group of up to 6 ring atoms; R19 is hydrogen, halogen, (C1C6)alkoxy, or (C1C6)alkyl.
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.
