title: Rapid assembly of diverse and potent allosteric Akt inhibitors.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., PO Box 4, West Point, PA 19486, USA. zhicai_wu@merck.com
authors.forename: Zhicai
authors.initials: Z
authors.lastname: Wu
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Robinson
authors.forename: Sheng
authors.initials: S
authors.lastname: Fu
authors.forename: Stanley F
authors.initials: SF
authors.lastname: Barnett
authors.forename: Deborah
authors.initials: D
authors.lastname: Defeo-Jones
authors.forename: Raymond E
authors.initials: RE
authors.lastname: Jones
authors.forename: Astrid M
authors.initials: AM
authors.lastname: Kral
authors.forename: Hans E
authors.initials: HE
authors.lastname: Huber
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Kohl
authors.forename: George D
authors.initials: GD
authors.lastname: Hartman
authors.forename: Mark T
authors.initials: MT
authors.lastname: Bilodeau
mesh_terms: 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
chemical_list: 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