title: Design, synthesis, and biological activity of novel, potent, and selective (benzoylaminomethyl)thiophene sulfonamide inhibitors of c-Jun-N-terminal kinase.
abstract: Several lines of evidence support the hypothesis that c-Jun N-terminal kinases (JNKs) play a critical role in a wide range of disease states including cell death (apoptosis)-related and inflammatory disorders (epilepsy, brain, heart and renal ischemia, neurodegenerative diseases, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel syndrome). The screening of a compound collection led to the identification of a 2-(benzoylaminomethyl)thiophene sulfonamide (AS004509, compound I) as a potent and selective JNK inhibitor. Chemistry and structure--activity relationship (SAR) studies performed around this novel kinase-inhibiting motif indicated that the left and central parts of the molecule were instrumental to maintaining potency at the enzyme. Accordingly, we investigated the JNK-inhibiting properties of a number of variants of the right-hand moiety of the molecule, which led to the identification of 2-(benzoylaminomethyl)thiophene sulfonamide benzotriazole (AS600292, compound 50a), the first potent and selective JNK inhibitor of this class which demonstrates a protective action against neuronal cell death induced by growth factor and serum deprivation.
authors.affiliation: Serono Pharmaceutical Research Institute, 14 Chemin des Aulx, 1228 Plan-Les-Ouates, Geneva, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rückle
authors.forename: Marco
authors.initials: M
authors.lastname: Biamonte
authors.forename: Tania
authors.initials: T
authors.lastname: Grippi-Vallotton
authors.forename: Steve
authors.initials: S
authors.lastname: Arkinstall
authors.forename: Yves
authors.initials: Y
authors.lastname: Cambet
authors.forename: Montserrat
authors.initials: M
authors.lastname: Camps
authors.forename: Christian
authors.initials: C
authors.lastname: Chabert
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Church
authors.forename: Serge
authors.initials: S
authors.lastname: Halazy
authors.forename: Xuliang
authors.initials: X
authors.lastname: Jiang
authors.forename: Isabelle
authors.initials: I
authors.lastname: Martinou
authors.forename: Anthony
authors.initials: A
authors.lastname: Nichols
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sauer
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Gotteland
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology; D013876:Thiophenes / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D013449:Sulfonamides; D013876:Thiophenes; D048031:JNK Mitogen-Activated Protein Kinases