Design, synthesis, and biological activity of novel, potent, and selective (benzoylaminomethyl)thiophene sulfonamide inhibitors of c-Jun-N-terminal kinase.
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.
Rückle
Thomas
T
Serono Pharmaceutical Research Institute, 14 Chemin des Aulx, 1228 Plan-Les-Ouates, Geneva, Switzerland.
Biamonte
Marco
M
Grippi-Vallotton
Tania
T
Arkinstall
Steve
S
Cambet
Yves
Y
Camps
Montserrat
M
Chabert
Christian
C
Church
Dennis J
DJ
Halazy
Serge
S
Jiang
Xuliang
X
Martinou
Isabelle
I
Nichols
Anthony
A
Sauer
Wolfgang
W
Gotteland
Jean-Pierre
JP
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
D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D013449:Sulfonamides; D013876:Thiophenes; D048031:JNK Mitogen-Activated Protein Kinases