The imidazo[1,2-a]pyridine ring system as a scaffold for potent dual phosphoinositide-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitors

Markian M Stec; Kristin L Andrews; Yunxin Bo; Sean Caenepeel; Hongyu Liao; John McCarter; Erin L Mullady; Tisha San Miguel; Raju Subramanian; Nuria Tamayo; Douglas A Whittington; Ling Wang; Tian Wu; Leeanne P Zalameda; Nancy Zhang; Paul E Hughes; Mark H Norman

doi:10.1016/j.bmcl.2015.08.016

The imidazo[1,2-a]pyridine ring system as a scaffold for potent dual phosphoinositide-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitors

Bioorg Med Chem Lett. 2015 Oct 1;25(19):4136-42. doi: 10.1016/j.bmcl.2015.08.016. Epub 2015 Aug 8.

Authors

Markian M Stec¹, Kristin L Andrews², Yunxin Bo³, Sean Caenepeel⁴, Hongyu Liao³, John McCarter⁵, Erin L Mullady⁶, Tisha San Miguel⁵, Raju Subramanian⁷, Nuria Tamayo³, Douglas A Whittington⁸, Ling Wang⁴, Tian Wu⁹, Leeanne P Zalameda⁵, Nancy Zhang⁴, Paul E Hughes⁴, Mark H Norman³

Affiliations

¹ Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA. Electronic address: mstec@amgen.com.
² Department of Molecular Structure, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
³ Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
⁴ Department of Oncology, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
⁵ Department of High-Throughput Screening/Molecular Pharmacology, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
⁶ Department of High-Throughput Screening/Molecular Pharmacology, Amgen Inc., 360 Binney Street, Cambridge, MA 02142, USA.
⁷ Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
⁸ Department of Molecular Structure, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA.
⁹ Department of Basic Pharmaceutics, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.

PMID: 26298499
DOI: 10.1016/j.bmcl.2015.08.016

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.

Keywords: Affinity pocket; Imidazo[1,2-a]pyridine; Kinase inhibitor; Phosphoinositide 3-kinase; Ribose pocket; mTOR.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Crystallography, X-Ray
Dose-Response Relationship, Drug
Humans
Mice
Microsomes, Liver / chemistry
Microsomes, Liver / metabolism
Models, Molecular
Molecular Structure
Phosphatidylinositol 3-Kinases / metabolism
Phosphoinositide-3 Kinase Inhibitors*
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacology*
Pyridines / chemistry*
Rats
Structure-Activity Relationship
TOR Serine-Threonine Kinases / antagonists & inhibitors*
TOR Serine-Threonine Kinases / metabolism

Substances

Phosphoinositide-3 Kinase Inhibitors
Protein Kinase Inhibitors
Pyridines
TOR Serine-Threonine Kinases
imidazo(1,2-a)pyridine