Discovery of potent and cell-active allosteric dual Akt 1 and 2 inhibitors.
This paper describes the improvement of cell potency in a class of allosteric Akt 1 and 2 inhibitors. Key discoveries include identifying the solvent exposed region of the molecule and appending basic amines to enhance the physiochemical properties of the molecules. Findings from the structure-activity relationships are discussed.
Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., 3535 General Atomics Court, San Diego, CA 92129, USA. tony_siu@merck.com
Tony
T
Siu
Jun
J
Liang
Jeannie
J
Arruda
Yiwei
Y
Li
Raymond E
RE
Jones
Deborah
D
Defeo-Jones
Stanley F
SF
Barnett
Ronald G
RG
Robinson
D000495:Allosteric Site; D002626:Chemistry, Pharmaceutical / Q000379:methods; D002627:Chemistry, Physical / Q000379:methods; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D010766:Phosphorylation; D010879:Piperazines / Q000737:chemistry; D047428:Protein Kinase Inhibitors / Q000737:chemistry; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000737:chemistry; D012997:Solvents / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D010879:Piperazines; D047428:Protein Kinase Inhibitors; D012997:Solvents; D051057:Proto-Oncogene Proteins c-akt