title: The optimization of aminooxadiazoles as orally active inhibitors of Cdc7.
abstract: A series of aminooxadiazoles was optimized for inhibition of Cdc7. Early lead isoquinoline 1 suffered from modest cell potency (cellular IC50=0.71 μM measuring pMCM2), low selectivity against structurally related kinases, and high IV clearance in rats (CL=18 L/h/kg). Extensive optimization resulted in azaindole 26 (Cdc7 IC50=1.1 nM, pMCM2 IC50=32 nM) that demonstrated robust lowering of pMCM2 in a mouse pharmacodynamic (PD) model when dosed orally. Modifications to improve the pharmacokinetic profile of this series were guided by trapping experiments with glutathione in rat hepatocytes.
authors.affiliation: Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA. Electronic address: pharring@amgen.com.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Harrington
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Bourbeau
authors.forename: Christopher
authors.initials: C
authors.lastname: Fotsch
authors.forename: Michael
authors.initials: M
authors.lastname: Frohn
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Pickrell
authors.forename: Andreas
authors.initials: A
authors.lastname: Reichelt
authors.forename: Kelvin
authors.initials: K
authors.lastname: Sham
authors.forename: Aaron C
authors.initials: AC
authors.lastname: Siegmund
authors.forename: Julie M
authors.initials: JM
authors.lastname: Bailis
authors.forename: Tammy
authors.initials: T
authors.lastname: Bush
authors.forename: Sonia
authors.initials: S
authors.lastname: Escobar
authors.forename: Dean
authors.initials: D
authors.lastname: Hickman
authors.forename: Scott
authors.initials: S
authors.lastname: Heller
authors.forename: Faye
authors.initials: F
authors.lastname: Hsieh
authors.forename: Jessica N
authors.initials: JN
authors.lastname: Orf
authors.forename: Minqing
authors.initials: M
authors.lastname: Rong
authors.forename: Tisha
authors.initials: T
authors.lastname: San Miguel
authors.forename: Helming
authors.initials: H
authors.lastname: Tan
authors.forename: Leeanne
authors.initials: L
authors.lastname: Zalameda
authors.forename: John G
authors.initials: JG
authors.lastname: Allen
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D018797:Cell Cycle Proteins; D010069:Oxadiazoles; D047428:Protein Kinase Inhibitors; C068619:CDC7 protein, human; D017346:Protein Serine-Threonine Kinases
keywords: Azaindole; Cancer; Cdc7; Kinase inhibitor; MCM2