title: Development of pyridopyrimidines as potent Akt1/2 inhibitors.
abstract: This communication reports a new synthetic route of pyridopyrimidines to facilitate their structural optimization in a library fashion and describes the development of pyridopyrimidines that have excellent enzymatic and cell potency against Akt1 and Akt2. This series also shows a high level of selectivity over other closely related kinases and significantly improved caspase-3 activity with the more optimized compounds.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., PO Box 4, West Point, PA 19486, USA.
authors.forename: Zhicai
authors.initials: Z
authors.lastname: Wu
authors.forename: John C
authors.initials: JC
authors.lastname: Hartnett
authors.forename: Lou Anne
authors.initials: LA
authors.lastname: Neilson
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: George D
authors.initials: GD
authors.lastname: Hartman
authors.forename: Mark T
authors.initials: MT
authors.lastname: Bilodeau
mesh_terms: D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020128:Inhibitory Concentration 50; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology
chemical_list: D000588:Amines; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D053221:TNF-Related Apoptosis-Inducing Ligand; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3