title: Phosphoinositide-3-kinase inhibitors: evaluation of substituted alcohols as replacements for the piperazine sulfonamide portion of AMG 511.
abstract: Replacement of the piperazine sulfonamide portion of the PI3Kα inhibitor AMG 511 (1) with a range of aliphatic alcohols led to the identification of a truncated gem-dimethylbenzylic alcohol analog, 2-(5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-6-((5-fluoro-6-methoxypyridin-3-yl)amino)pyridin-3-yl)propan-2-ol (7). This compound possessed good in vitro efficacy and pharmacokinetic parameters and demonstrated an EC50 of 239 ng/mL in a mouse liver pharmacodynamic model measuring the inhibition of hepatocyte growth factor (HGF)-induced Akt Ser473 phosphorylation in CD1 nude mice 6 h post-oral dosing.
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States. Electronic address: blanman@amgen.com.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Lanman
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States.
authors.forename: Anthony B
authors.initials: AB
authors.lastname: Reed
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States.
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Cee
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States.
authors.forename: Fang-Tsao
authors.initials: FT
authors.lastname: Hong
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States.
authors.forename: Liping H
authors.initials: LH
authors.lastname: Pettus
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States.
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Wurz
authors.affiliation: Department of Molecular Structure, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States.
authors.forename: Kristin L
authors.initials: KL
authors.lastname: Andrews
authors.affiliation: Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States.
authors.forename: Jian
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Department of High-Throughput Screening/Molecular Pharmacology, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States.
authors.forename: John D
authors.initials: JD
authors.lastname: McCarter
authors.affiliation: Department of High-Throughput Screening/Molecular Pharmacology, Amgen Inc., 360 Binney Street, Cambridge, MA 02142, United States.
authors.forename: Erin L
authors.initials: EL
authors.lastname: Mullady
authors.affiliation: Department of High-Throughput Screening/Molecular Pharmacology, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States.
authors.forename: Tisha
authors.initials: T
authors.lastname: San Miguel
authors.affiliation: Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States.
authors.forename: Raju
authors.initials: R
authors.lastname: Subramanian
authors.affiliation: Department of Oncology Research, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States.
authors.forename: Ling
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Molecular Structure, Amgen Inc., 360 Binney Street, Cambridge, MA 02142, United States.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Whittington
authors.affiliation: Department of Pharmaceutics, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States.
authors.forename: Tian
authors.initials: T
authors.lastname: Wu
authors.affiliation: Department of High-Throughput Screening/Molecular Pharmacology, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States.
authors.forename: Leeanne
authors.initials: L
authors.lastname: Zalameda
authors.affiliation: Department of Oncology Research, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States.
authors.forename: Nancy
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Tasker
authors.affiliation: Department of Oncology Research, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Hughes
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States.
authors.forename: Mark H
authors.initials: MH
authors.lastname: Norman
mesh_terms: D000438:Alcohols / Q000737:chemistry*; D000818:Animals; D005260:Female; D006207:Half-Life; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008968:Molecular Conformation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D000077489:Piperazine; D010879:Piperazines / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D014227:Triazines / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics
chemical_list: D000438:Alcohols; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D000077489:Piperazine; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011725:Pyridines; D013449:Sulfonamides; D058570:TOR Serine-Threonine Kinases; D014227:Triazines; C000599485:2-(5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-6-((5-fluoro-6-methoxypyridin-3-yl)amino)pyridin-3-yl)propan-2-ol; C000599486:AMG 511
keywords: Kinase inhibitor; Ligand efficiency; Phosphoinositide-3-kinase-alpha; Protein kinase B; Ribose pocket