title: Synthesis and evaluation of heteroaryl-ketone derivatives as a novel class of VEGFR-2 inhibitors.
abstract: We have discovered novel inhibitors of VEGFR-2 kinase with low nanomolar potency in both enzymatic and cell-based assays. Active series are heteroaryl-ketone compounds containing a central aromatic ring with either an indazolyl or indolyl keto group in the ortho orientation to the benzylic amine group (Fig. 1). The best compounds were demonstrated to be inactive against a small select panel of tyrosine and serine/threonine kinases with the exception of VEGFR-1 kinase, a close family member. In addition, the lead candidate 8 displayed acceptable exposure levels when administered orally to mice.
authors.affiliation: Department of Chemistry, ImClone Systems Incorporated, New York, NY 10014, USA. piatnits@gmail.com
authors.forename: Eugene L
authors.initials: EL
authors.lastname: Piatnitski Chekler
authors.forename: Reeti
authors.initials: R
authors.lastname: Katoch-Rouse
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Kiselyov
authors.forename: Dan
authors.initials: D
authors.lastname: Sherman
authors.forename: Xiaohu
authors.initials: X
authors.lastname: Ouyang
authors.forename: Ki
authors.initials: K
authors.lastname: Kim
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Yaron R
authors.initials: YR
authors.lastname: Hadari
authors.forename: Jacqueline F
authors.initials: JF
authors.lastname: Doody
mesh_terms: D000284:Administration, Oral; D000818:Animals; D020650:Combinatorial Chemistry Techniques; D020128:Inhibitory Concentration 50; D007659:Ketones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D015394:Molecular Structure; D010880:Piperidines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D013329:Structure-Activity Relationship; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
chemical_list: D007659:Ketones; D010880:Piperidines; D011799:Quinazolines; D040301:Vascular Endothelial Growth Factor Receptor-2; C452423:vandetanib