Rapid assembly of diverse and potent allosteric Akt inhibitors.
This paper describes the rapid assembly of four different classes of potent Akt inhibitors from a common intermediate. Among them, a pyridopyrimidine series displayed the best intrinsic and cell potency against Akt1 and Akt2. This series also showed a promising pharmacokinetic profile and excellent selectivity over other closely related kinases.
Wu
Zhicai
Z
Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., PO Box 4, West Point, PA 19486, USA. zhicai_wu@merck.com
Robinson
Ronald G
RG
Fu
Sheng
S
Barnett
Stanley F
SF
Defeo-Jones
Deborah
D
Jones
Raymond E
RE
Kral
Astrid M
AM
Huber
Hans E
HE
Kohl
Nancy E
NE
Hartman
George D
GD
Bilodeau
Mark T
MT
D000495:Allosteric Site; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D004285:Dogs; D005260:Female; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D015394:Molecular Structure; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry*; D011743:Pyrimidines / Q000737:chemistry*; D013329:Structure-Activity Relationship; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases