title: Tri- and tetrasubstituted pyrazole derivates: regioisomerism switches activity from p38MAP kinase to important cancer kinases.
abstract: In the course of searching for new p38α MAP kinase inhibitors, we found that the regioisomeric switch from 3-(4-fluorophenyl)-4-(pyridin-4-yl)-1-(aryl)-1H-pyrazol-5-amine to 4-(4-fluorophenyl)-3-(pyridin-4-yl)-1-(aryl)-1H-pyrazol-5-amine led to an almost complete loss of p38α inhibition, but they showed activity against important cancer kinases. Among the tested derivatives, 4-(4-fluorophenyl)-3-(pyridin-4-yl)-1-(2,4,6-trichlorophenyl)-1H-pyrazol-5-amine (6a) exhibited the best activity, with IC(50) in the nanomolar range against Src, B-Raf wt, B-Raf V600E, EGFRs, and VEGFR-2, making it a good lead for novel anticancer programs.
authors.affiliation: Faculty of Science, Chemistry Department, Islamic University of Gaza, Gaza Strip, Palestine.
authors.forename: Bassam
authors.initials: B
authors.lastname: Abu Thaher
authors.forename: Martina
authors.initials: M
authors.lastname: Arnsmann
authors.forename: Frank
authors.initials: F
authors.lastname: Totzke
authors.forename: Jan E
authors.initials: JE
authors.lastname: Ehlert
authors.forename: Michael H G
authors.initials: MH
authors.lastname: Kubbutat
authors.forename: Christoph
authors.initials: C
authors.lastname: Schächtele
authors.forename: Markus O
authors.initials: MO
authors.lastname: Zimmermann
authors.forename: Pierre
authors.initials: P
authors.lastname: Koch
authors.forename: Frank M
authors.initials: FM
authors.lastname: Boeckler
authors.forename: Stefan A
authors.initials: SA
authors.lastname: Laufer
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry; D057075:Enzyme Assays; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics; D008958:Models, Molecular; D009154:Mutation; D009369:Neoplasms / Q000201:enzymology*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D066246:ErbB Receptors; D040301:Vascular Endothelial Growth Factor Receptor-2; D019061:src-Family Kinases; D048493:Proto-Oncogene Proteins B-raf; D048051:p38 Mitogen-Activated Protein Kinases