The design and synthesis of potent and cell-active allosteric dual Akt 1 and 2 inhibitors devoid of hERG activity.
This letter details the attenuation of hERG in a class of Akt inhibitors through heteroatom insertions into aromatic rings. The development of a cell-active dual Akt 1 and 2 inhibitors devoid of hERG activity is discussed using structure-activity relationships.
Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., 3535 General Atomics Court, San Diego, CA 92129, USA. address: tony_siu@merck.com
Tony
T
Siu
Yiwei
Y
Li
Johnny
J
Nagasawa
Jun
J
Liang
Lida
L
Tehrani
Peter
P
Chua
Raymond E
RE
Jones
Deborah
D
Defeo-Jones
Stanley F
SF
Barnett
Ronald G
RG
Robinson
D000494:Allosteric Regulation; D000495:Allosteric Site; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D000072237:ERG1 Potassium Channel; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051638:Ether-A-Go-Go Potassium Channels / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D000072237:ERG1 Potassium Channel; D004791:Enzyme Inhibitors; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D051057:Proto-Oncogene Proteins c-akt