title: Discovery and evaluation of 3-(5-thien-3-ylpyridin-3-yl)-1H-indoles as a novel class of KDR kinase inhibitors.
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.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. mark_fraley@merck.com
authors.forename: Mark E
authors.initials: ME
authors.lastname: Fraley
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Arrington
authors.forename: Scott R
authors.initials: SR
authors.lastname: Hambaugh
authors.forename: William F
authors.initials: WF
authors.lastname: Hoffman
authors.forename: April M
authors.initials: AM
authors.lastname: Cunningham
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Young
authors.forename: Randall W
authors.initials: RW
authors.lastname: Hungate
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Tebben
authors.forename: Ruth Z
authors.initials: RZ
authors.lastname: Rutledge
authors.forename: Richard L
authors.initials: RL
authors.lastname: Kendall
authors.forename: William R
authors.initials: WR
authors.lastname: Huckle
authors.forename: Rosemary C
authors.initials: RC
authors.lastname: McFall
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: Coll
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Thomas
mesh_terms: D000284:Administration, Oral; D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D002460:Cell Line; D006207:Half-Life; D007211:Indoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D051381:Rats; D013329:Structure-Activity Relationship; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
chemical_list: D020533:Angiogenesis Inhibitors; D007211:Indoles; D040301:Vascular Endothelial Growth Factor Receptor-2