Design, synthesis and SAR of substituted indoles as selective TrkA inhibitors

Danielle M Hurzy; Darrell A Henze; Tamara D Cabalu; Kartik Narayan; Amanda Heller; Andrew J Cooke

doi:10.1016/j.bmcl.2017.04.045

Design, synthesis and SAR of substituted indoles as selective TrkA inhibitors

Bioorg Med Chem Lett. 2017 Jun 15;27(12):2695-2701. doi: 10.1016/j.bmcl.2017.04.045. Epub 2017 Apr 20.

Authors

Danielle M Hurzy¹, Darrell A Henze², Tamara D Cabalu³, Kartik Narayan⁴, Amanda Heller⁵, Andrew J Cooke⁶

Affiliations

¹ Department of Medicinal Chemistry, MRL, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA. Electronic address: danielle_mcmaster@merck.com.
² Department of Pain Research, MRL, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA.
³ Department of Drug Metabolism, MRL, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA.
⁴ Analytical Process and Technology, Sanofi Pasteur, Discovery Drive, Swiftwater, PA 18370, USA.
⁵ Scientific Operations, Lab Connect, LLC., 605 First Avenue, Ste. 300, Seattle, WA 98104, USA.
⁶ Department of Medicinal Chemistry, MRL, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA.

PMID: 28465100
DOI: 10.1016/j.bmcl.2017.04.045

Abstract

A series of substituted indoles were examined as selective inhibitors of tropomyosin-related kinase receptor A (TrkA), a therapeutic target for the treatment of pain. An SAR optimization campaign based on ALIS screening lead compound 1 is reported.

Keywords: Indoles; Pain; TrkA.

MeSH terms

Dose-Response Relationship, Drug
Drug Design*
Humans
Indoles / chemical synthesis
Indoles / chemistry
Indoles / pharmacology*
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Receptor, trkA / antagonists & inhibitors*
Receptor, trkA / metabolism
Structure-Activity Relationship

Substances

Indoles
NTRK1 protein, human
Protein Kinase Inhibitors
Receptor, trkA