Potent and cellularly active 4-aminoimidazole inhibitors of cyclin-dependent kinase 5/p25 for the treatment of Alzheimer's disease.
Utilizing structure-based drug design, a 4-aminoimidazole heterocyclic core was synthesized as a replacement for a 2-aminothiazole due to potential metabolically mediated toxicity. The synthetic route utilized allowed for ready synthesis of 1-substituted-4-aminoimidazoles. SAR exploration resulted in the identification of a novel cis-substituted cyclobutyl group that gave improved enzyme and cellular potency against cdk5/p25 with up to 30-fold selectivity over cdk2/cyclin E.
Helal
Christopher J
CJ
Neuroscience Medicinal Chemistry, Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA. chris.j.helal@pfizer.com
Kang
Zhijun
Z
Lucas
John C
JC
Gant
Thomas
T
Ahlijanian
Michael K
MK
Schachter
Joel B
JB
Richter
Karl E G
KE
Cook
James M
JM
Menniti
Frank S
FS
Kelly
Kristin
K
Mente
Scot
S
Pandit
Jay
J
Hosea
Natalie
N
D000544:Alzheimer Disease / Q000188:drug therapy*; D000818:Animals; D001665:Binding Sites; D018938:Caco-2 Cells; D018360:Crystallography, X-Ray; D019927:Cyclin E / Q000037:antagonists & inhibitors / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015195:Drug Design; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D019927:Cyclin E; D007093:Imidazoles; D009419:Nerve Tissue Proteins; D047428:Protein Kinase Inhibitors; C118136:TPPP protein, human; C098330:4-aminoimidazole; D051360:Cyclin-Dependent Kinase 5; D051357:Cyclin-Dependent Kinase 2