title: The imidazo[1,2-a]pyridine ring system as a scaffold for potent dual phosphoinositide-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitors.
abstract: Based on lead compound 1, which was discovered from a high-throughput screen, a series of PI3Kα/mTOR inhibitors were evaluated that contained an imidazo[1,2-a]pyridine as a core replacement for the benzimidazole contained in 1. By exploring various ring systems that occupy the affinity pocket, two fragments containing a methoxypyridine were identified that gave <100 nM potency toward PI3Kα in enzyme and cellular assays with moderate stability in rat and human liver microsomes. With the two methoxypyridine groups selected to occupy the affinity pocket, analogs were prepared with various fragments intended to occupy the ribose pocket of PI3Kα and mTOR. From these analogs, tertiary alcohol 18 was chosen for in vivo pharmacodynamic evaluation based on its potency in the PI3Kα cellular assay, microsomal stability, and in vivo pharmacokinetic properties. In a mouse liver pharmacodynamic assay, compound 18 showed 56% inhibition of HFG-induced AKT (Ser473) phosphorylation at a 30 mg/kg dose.
authors: Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA. Electronic address: mstec@amgen.com.
authors: Markian M
authors: MM
authors: Stec
authors: Department of Molecular Structure, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors: Kristin L
authors: KL
authors: Andrews
authors: Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors: Yunxin
authors: Y
authors: Bo
authors: Department of Oncology, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors: Sean
authors: S
authors: Caenepeel
authors: Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors: Hongyu
authors: H
authors: Liao
authors: Department of High-Throughput Screening/Molecular Pharmacology, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors: John
authors: J
authors: McCarter
authors: Department of High-Throughput Screening/Molecular Pharmacology, Amgen Inc., 360 Binney Street, Cambridge, MA 02142, USA.
authors: Erin L
authors: EL
authors: Mullady
authors: Department of High-Throughput Screening/Molecular Pharmacology, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors: Tisha
authors: T
authors: San Miguel
authors: Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors: Raju
authors: R
authors: Subramanian
authors: Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors: Nuria
authors: N
authors: Tamayo
authors: Department of Molecular Structure, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA.
authors: Douglas A
authors: DA
authors: Whittington
authors: Department of Oncology, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors: Ling
authors: L
authors: Wang
authors: Department of Basic Pharmaceutics, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors: Tian
authors: T
authors: Wu
authors: Department of High-Throughput Screening/Molecular Pharmacology, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors: Leeanne P
authors: LP
authors: Zalameda
authors: Department of Oncology, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors: Nancy
authors: N
authors: Zhang
authors: Department of Oncology, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors: Paul E
authors: PE
authors: Hughes
authors: Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors: Mark H
authors: MH
authors: Norman
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051379:Mice; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011725:Pyridines / Q000737:chemistry*; D051381:Rats; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D058570:TOR Serine-Threonine Kinases; C001439:imidazo(1,2-a)pyridine
keywords: Affinity pocket; Imidazo[1,2-a]pyridine; Kinase inhibitor; Phosphoinositide 3-kinase; Ribose pocket; mTOR