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.

BMP2 induction of actin cytoskeleton reorganization and cell migration requires PI3-kinase and Cdc42 activity

“…Since LY294002 is not selective among the members of the class I PI3Ks (Hawkins et al, 2006), we used a set of recently developed isoformselective class I PI3K inhibitors (Camps et al, 2005;Jackson et al, 2005;Pomel et al, 2006;Sadhu et al, 2003). Cells were treated with either the PI3Kγ-selective inhibitor AS252424 (Pomel et al, 2006), the PI3Kβ-selective inhibitor TGX-155 (Jackson et al, 2005), the PI3Kδ-selective inhibitor IC87114 (Billottet et al, 2006;Sadhu et al, 2003) or the PI3Kα-selective inhibitor AS702630 (Ruckle et al, 2004), and analyzed phosphorylation of Akt after stimulated with BMP2 for different times. BMP2-mediated Akt phosphorylation was abolished only in cells pretreated with AS702630, but not with any other of the selective inhibitors used, suggesting that, in C2C12 cells, BMP2 induced Akt phosphorylation through the specific activation of the PI3Kα isoform (Fig.…”

Small Molecular Weight Inhibitors of Stress-Activated and Mitogen- Activated Protein Kinases

“…Nevertheless, JNK inhibition resulted in a delay of the loss of hippocampal neurons characteristic of transient global ischemia. The significant reduction in neuronal apoptosis after administration of AS601245 or AS6010292 [2-benzoylaminoethyl) thiophene sulfonamide benzotriazole] [27,28] in either the focal or global cerebral ischemia model in gerbils, suggested that AS601245 was a "neuroprotectant" and therefore was of considerable interest as a potential novel therapy for stroke and Parkinson's disease [28]. AS601245 was shown to inhibit JNK-1, -2, and 3 with IC 50 values of 0.15, 0.22 and 0.07 µM, respectively using in vitro PK assays [29].…”

Small Molecule Drug Discovery in the Fast-Changing World of Biotechnology

“…Screening of our compound collection for inhibitors of JNK3 identified several promising starting points that were subsequently optimized for potency, selectivity, and biopharmaceutical profile [23][24][25][26]. One compound emerging from these efforts has entered human clinical trials earlier this year, and several back-up molecules are currently progressing in late-stage preclinical development.…”