Discovery and evaluation of 3-(5-thien-3-ylpyridin-3-yl)-1H-indoles as a novel class of KDR kinase inhibitors

Mark E Fraley; Kenneth L Arrington; Scott R Hambaugh; William F Hoffman; April M Cunningham; Mary Beth Young; Randall W Hungate; Andrew J Tebben; Ruth Z Rutledge; Richard L Kendall; William R Huckle; Rosemary C McFall; Kathleen E Coll; Kenneth A Thomas

doi:10.1016/s0960-894x(03)00627-9

Discovery and evaluation of 3-(5-thien-3-ylpyridin-3-yl)-1H-indoles as a novel class of KDR kinase inhibitors

Bioorg Med Chem Lett. 2003 Sep 15;13(18):2973-6. doi: 10.1016/s0960-894x(03)00627-9.

Authors

Mark E Fraley¹, Kenneth L Arrington, Scott R Hambaugh, William F Hoffman, April M Cunningham, Mary Beth Young, Randall W Hungate, Andrew J Tebben, Ruth Z Rutledge, Richard L Kendall, William R Huckle, Rosemary C McFall, Kathleen E Coll, Kenneth A Thomas

Affiliation

¹ Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. mark_fraley@merck.com

PMID: 12941314
DOI: 10.1016/s0960-894x(03)00627-9

Abstract

We have discovered 3-(5-thien-3-ylpyridin-3-yl)-1H-indoles as potent inhibitors of KDR kinase activity. This communication details the evolution of this novel class from a potent screening lead of vastly different structure with an emphasis on structural modifications that retained activity and provided improvements in key physical properties. The synthesis and in-depth evaluation of these inhibitors are described.

MeSH terms

Administration, Oral
Angiogenesis Inhibitors / chemical synthesis*
Angiogenesis Inhibitors / pharmacokinetics
Angiogenesis Inhibitors / pharmacology
Animals
Biological Availability
Cell Line
Half-Life
Indoles / chemical synthesis*
Indoles / pharmacokinetics*
Indoles / pharmacology
Inhibitory Concentration 50
Rats
Structure-Activity Relationship
Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*

Substances

Angiogenesis Inhibitors
Indoles
Vascular Endothelial Growth Factor Receptor-2