PMID- 26298499
OWN - NLM
STAT- MEDLINE
DCOM- 20160523
LR  - 20211203
IS  - 1464-3405 (Electronic)
IS  - 0960-894X (Linking)
VI  - 25
IP  - 19
DP  - 2015 Oct 1
TI  - The imidazo[1,2-a]pyridine ring system as a scaffold for potent dual 
      phosphoinositide-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitors.
PG  - 4136-42
LID - S0960-894X(15)00840-9 [pii]
LID - 10.1016/j.bmcl.2015.08.016 [doi]
AB  - Based on lead compound 1, which was discovered from a high-throughput screen, a 
      series of PI3Kalpha/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 PI3Kalpha 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 PI3Kalpha and mTOR. From these analogs, tertiary alcohol 
      18 was chosen for in vivo pharmacodynamic evaluation based on its potency in the 
      PI3Kalpha 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.
CI  - Copyright (c) 2015 Elsevier Ltd. All rights reserved.
FAU - Stec, Markian M
AU  - Stec MM
AD  - Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand 
      Oaks, CA 91320-1799, USA. Electronic address: mstec@amgen.com.
FAU - Andrews, Kristin L
AU  - Andrews KL
AD  - Department of Molecular Structure, Amgen Inc., One Amgen Center Drive, Thousand 
      Oaks, CA 91320-1799, USA.
FAU - Bo, Yunxin
AU  - Bo Y
AD  - Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand 
      Oaks, CA 91320-1799, USA.
FAU - Caenepeel, Sean
AU  - Caenepeel S
AD  - Department of Oncology, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 
      91320-1799, USA.
FAU - Liao, Hongyu
AU  - Liao H
AD  - Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand 
      Oaks, CA 91320-1799, USA.
FAU - McCarter, John
AU  - McCarter J
AD  - Department of High-Throughput Screening/Molecular Pharmacology, Amgen Inc., One 
      Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
FAU - Mullady, Erin L
AU  - Mullady EL
AD  - Department of High-Throughput Screening/Molecular Pharmacology, Amgen Inc., 360 
      Binney Street, Cambridge, MA 02142, USA.
FAU - San Miguel, Tisha
AU  - San Miguel T
AD  - Department of High-Throughput Screening/Molecular Pharmacology, Amgen Inc., One 
      Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
FAU - Subramanian, Raju
AU  - Subramanian R
AD  - Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., One Amgen Center 
      Drive, Thousand Oaks, CA 91320-1799, USA.
FAU - Tamayo, Nuria
AU  - Tamayo N
AD  - Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand 
      Oaks, CA 91320-1799, USA.
FAU - Whittington, Douglas A
AU  - Whittington DA
AD  - Department of Molecular Structure, Amgen Inc., 360 Binney St., Cambridge, MA 
      02142, USA.
FAU - Wang, Ling
AU  - Wang L
AD  - Department of Oncology, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 
      91320-1799, USA.
FAU - Wu, Tian
AU  - Wu T
AD  - Department of Basic Pharmaceutics, Amgen Inc., One Amgen Center Drive, Thousand 
      Oaks, CA 91320-1799, USA.
FAU - Zalameda, Leeanne P
AU  - Zalameda LP
AD  - Department of High-Throughput Screening/Molecular Pharmacology, Amgen Inc., One 
      Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
FAU - Zhang, Nancy
AU  - Zhang N
AD  - Department of Oncology, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 
      91320-1799, USA.
FAU - Hughes, Paul E
AU  - Hughes PE
AD  - Department of Oncology, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 
      91320-1799, USA.
FAU - Norman, Mark H
AU  - Norman MH
AD  - Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand 
      Oaks, CA 91320-1799, USA.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150808
PL  - England
TA  - Bioorg Med Chem Lett
JT  - Bioorganic & medicinal chemistry letters
JID - 9107377
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Pyridines)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - G18ZBV2HXA (imidazo(1,2-a)pyridine)
SB  - IM
MH  - Animals
MH  - Crystallography, X-Ray
MH  - Dose-Response Relationship, Drug
MH  - Humans
MH  - Mice
MH  - Microsomes, Liver/chemistry/metabolism
MH  - Models, Molecular
MH  - Molecular Structure
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - *Phosphoinositide-3 Kinase Inhibitors
MH  - Protein Kinase Inhibitors/chemical synthesis/*chemistry/*pharmacology
MH  - Pyridines/*chemistry
MH  - Rats
MH  - Structure-Activity Relationship
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors/metabolism
OTO - NOTNLM
OT  - Affinity pocket
OT  - Imidazo[1,2-a]pyridine
OT  - Kinase inhibitor
OT  - Phosphoinositide 3-kinase
OT  - Ribose pocket
OT  - mTOR
EDAT- 2015/08/25 06:00
MHDA- 2016/05/24 06:00
CRDT- 2015/08/24 06:00
PHST- 2015/06/13 00:00 [received]
PHST- 2015/08/02 00:00 [revised]
PHST- 2015/08/06 00:00 [accepted]
PHST- 2015/08/24 06:00 [entrez]
PHST- 2015/08/25 06:00 [pubmed]
PHST- 2016/05/24 06:00 [medline]
AID - S0960-894X(15)00840-9 [pii]
AID - 10.1016/j.bmcl.2015.08.016 [doi]
PST - ppublish
SO  - Bioorg Med Chem Lett. 2015 Oct 1;25(19):4136-42. doi: 10.1016/j.bmcl.2015.08.016. 
      Epub 2015 Aug 8.