Discovery, synthesis and characterization of a series of 7-aryl-imidazo[1,2-a]pyridine-3-ylquinolines as activin-like kinase (ALK) inhibitors

Darren W Engers; Sean R Bollinger; Andrew S Felts; Anish K Vadukoot; Charles H Williams; Anna L Blobaum; Craig W Lindsley; Charles C Hong; Corey R Hopkins

doi:10.1016/j.bmcl.2020.127418

Discovery, synthesis and characterization of a series of 7-aryl-imidazo[1,2-a]pyridine-3-ylquinolines as activin-like kinase (ALK) inhibitors

Bioorg Med Chem Lett. 2020 Sep 15;30(18):127418. doi: 10.1016/j.bmcl.2020.127418. Epub 2020 Jul 17.

Authors

Darren W Engers¹, Sean R Bollinger¹, Andrew S Felts¹, Anish K Vadukoot², Charles H Williams³, Anna L Blobaum¹, Craig W Lindsley⁴, Charles C Hong³, Corey R Hopkins⁵

Affiliations

¹ Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA.
² Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198-6125, USA.
³ Division of Cardiovascular Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
⁴ Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA; Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA.
⁵ Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198-6125, USA. Electronic address: corey.hopkins@unmc.edu.

Abstract

The activin-like kinases are a family of kinases that play important roles in a variety of disease states. Of this class of kinases, ALK2, has been shown by a gain-of-function to be the primary driver of the childhood skeletal disease fibrodysplasia ossificans progressiva (FOP) and more recently the pediatric cancer diffuse intrinsic pontine glioma (DIPG). Herein, we report our efforts to identify a novel imidazo[1,2-a]pyridine scaffold as potent inhibitors of ALK2 with good in vivo pharmacokinetic properties suitable for future animal studies.

Keywords: ALK2; ALK3; Activin-like kinase inhibitors; BMP inhibitors.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Activin Receptors, Type I / antagonists & inhibitors*
Animals
Child
Diffuse Intrinsic Pontine Glioma / drug therapy*
Drug Discovery
Humans
Imidazolines / chemistry
Microsomes, Liver / drug effects
Mutation
Myositis Ossificans / drug therapy*
Protein Kinase Inhibitors / chemical synthesis*
Protein Kinase Inhibitors / pharmacokinetics
Pyridines / chemistry
Quinolines / chemical synthesis*
Quinolines / pharmacokinetics
Rats
Signal Transduction
Structure-Activity Relationship

Substances

Imidazolines
Protein Kinase Inhibitors
Pyridines
Quinolines
ACVR1 protein, human
Activin Receptors, Type I

Grants and funding

R01 GM118557/GM/NIGMS NIH HHS/United States