title: Optimization of 2,3,5-trisubstituted pyridine derivatives as potent allosteric Akt1 and Akt2 inhibitors.
abstract: This letter shows inhibitor SAR on a pyridine series of allosteric Akt inhibitors to optimize enzymatic and cellular potency. We have optimized 2,3,5-trisubstituted pyridines to give potent Akt1 and Akt2 inhibitors in both enzyme and cell based assays. In addition, we will also highlight the pharmacokinetic profile of an optimized inhibitor that has low clearance and long half-life in dogs.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., PO Box 4, West Point, PA 19486, USA. john_hartnett@merck.com
authors.forename: John C
authors.initials: JC
authors.lastname: Hartnett
authors.forename: Stanley F
authors.initials: SF
authors.lastname: Barnett
authors.forename: Mark T
authors.initials: MT
authors.lastname: Bilodeau
authors.forename: Deborah
authors.initials: D
authors.lastname: Defeo-Jones
authors.forename: George D
authors.initials: GD
authors.lastname: Hartman
authors.forename: Hans E
authors.initials: HE
authors.lastname: Huber
authors.forename: Raymond E
authors.initials: RE
authors.lastname: Jones
authors.forename: Astrid M
authors.initials: AM
authors.lastname: Kral
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Robinson
authors.forename: Zhicai
authors.initials: Z
authors.lastname: Wu
mesh_terms: D000495:Allosteric Site; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D004285:Dogs; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D015394:Molecular Structure; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / 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; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases; C023666:pyridine