Synthesis and structure-activity relationship of 4-(1,3-benzothiazol-2-yl)-thiophene-2-sulfonamides as cyclin-dependent kinase 5 (cdk5)/p25 inhibitors.
4-(1,3-Benzothiazol-2-yl)thiophene-2-sulfonamide (4a) was found to be a moderately potent inhibitor of cyclin-dependent kinase 5 (cdk5) from a HTS screen. The synthesis and SAR around this hit is described. The X-ray coordinates of ligand 4a with cdk5 are also reported, showing an unusual binding mode to the hinge region via a water molecule.
Medicinal Chemistry, CNSP iMed Science, AstraZeneca R&D, Innovative Medicines, SE-15185 Södertälje, Sweden. Jonas.Malmstrom@astrazeneca.com
Jonas
J
Malmström
Jenny
J
Viklund
Can
C
Slivo
Ana
A
Costa
Mickaël
M
Maudet
Catrin
C
Sandelin
Gösta
G
Hiller
Lise-Lotte
LL
Olsson
Anna
A
Aagaard
Stefan
S
Geschwindner
Yafeng
Y
Xue
Mervi
M
Vasänge
D018360:Crystallography, X-Ray; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D008958:Models, Molecular; D015394:Molecular Structure; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
C576868:4-(1,3-benzothiazol-2-yl)thiophene-2-sulfonamide; D009419:Nerve Tissue Proteins; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D013876:Thiophenes; C089495:neuronal Cdk5 activator (p25-p35); D051360:Cyclin-Dependent Kinase 5