Brain penetrant kinase inhibitors: Learning from kinase neuroscience discovery

Yuan Shi; Mary Mader

doi:10.1016/j.bmcl.2018.05.007

Brain penetrant kinase inhibitors: Learning from kinase neuroscience discovery

Bioorg Med Chem Lett. 2018 Jun 15;28(11):1981-1991. doi: 10.1016/j.bmcl.2018.05.007. Epub 2018 May 4.

Authors

Yuan Shi¹, Mary Mader²

Affiliations

¹ Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
² Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. Electronic address: mader@lilly.com.

PMID: 29752185
DOI: 10.1016/j.bmcl.2018.05.007

Abstract

A recent review of kinase inhibitors in clinical trials for brain cancer noted differences in the properties of these compounds relative to the mean property parameters associated with drugs marketed for CNS-associated conditions. However, many of these kinase drugs arose from opportunistic observations of brain activity, rather than design or flow schemes focused on optimizing CNS penetration. Thus, this digest examines kinase inhibitors that have been developed specifically for neurodegenerative indications such as Alzheimer's or Parkinson's disease, and considers design, flow scheme, and the physicochemical properties associated with compounds that have demonstrated brain penetrance.

Keywords: Alzheimer’s disease; Brain penetrant; Kinase inhibitor; Neurodegeneration; Parkinson’s disease.

Publication types

Review

MeSH terms

Animals
Drug Discovery*
Humans
Neurodegenerative Diseases / drug therapy*
Neurodegenerative Diseases / metabolism
Neuroprotective Agents / chemical synthesis
Neuroprotective Agents / chemistry
Neuroprotective Agents / pharmacology*
Neurosciences
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Protein Kinases / metabolism*

Substances

Neuroprotective Agents
Protein Kinase Inhibitors
Protein Kinases