title: Alkynylpyrimidine amide derivatives as potent, selective, and orally active inhibitors of Tie-2 kinase.
abstract: The recognition that aberrant angiogenesis contributes to the pathology of inflammatory diseases, cancer, and myocardial ischemia has generated considerable interest in the molecular mechanisms that regulate blood vessel growth. The receptor tyrosine kinase Tie-2 is expressed primarily by vascular endothelial cells and is critical for embryonic vasculogenesis. Interference with the Tie-2 pathway by diverse blocking agents such as soluble Tie-2 receptors, anti-Tie-2 intrabodies, anti-Ang-2 antibodies, and peptide-Fc conjugates has been shown to suppress tumor growth in xenograft studies. An alternative strategy for interfering with the Tie-2 signaling pathway involves direct inhibition of the kinase functions of the Tie-2 receptor. Herein we describe the development of alkynylpyrimidine amide derivatives as potent, selective, and orally available ATP-competitive inhibitors of Tie-2 autophosphorylation.
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., One Kendall Square, Bldg. 1000, Cambridge, Massachusetts 02139, USA. vcee@amgen.com
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Cee
authors.forename: Brian K
authors.initials: BK
authors.lastname: Albrecht
authors.forename: Stephanie
authors.initials: S
authors.lastname: Geuns-Meyer
authors.forename: Paul
authors.initials: P
authors.lastname: Hughes
authors.forename: Steve
authors.initials: S
authors.lastname: Bellon
authors.forename: James
authors.initials: J
authors.lastname: Bready
authors.forename: Sean
authors.initials: S
authors.lastname: Caenepeel
authors.forename: Stuart C
authors.initials: SC
authors.lastname: Chaffee
authors.forename: Angela
authors.initials: A
authors.lastname: Coxon
authors.forename: Maurice
authors.initials: M
authors.lastname: Emery
authors.forename: Jenne
authors.initials: J
authors.lastname: Fretland
authors.forename: Paul
authors.initials: P
authors.lastname: Gallant
authors.forename: Yan
authors.initials: Y
authors.lastname: Gu
authors.forename: Brian L
authors.initials: BL
authors.lastname: Hodous
authors.forename: Doug
authors.initials: D
authors.lastname: Hoffman
authors.forename: Rebecca E
authors.initials: RE
authors.lastname: Johnson
authors.forename: Richard
authors.initials: R
authors.lastname: Kendall
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Kim
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Long
authors.forename: David
authors.initials: D
authors.lastname: McGowan
authors.forename: Michael
authors.initials: M
authors.lastname: Morrison
authors.forename: Philip R
authors.initials: PR
authors.lastname: Olivieri
authors.forename: Vinod F
authors.initials: VF
authors.lastname: Patel
authors.forename: Anthony
authors.initials: A
authors.lastname: Polverino
authors.forename: David
authors.initials: D
authors.lastname: Powers
authors.forename: Paul
authors.initials: P
authors.lastname: Rose
authors.forename: Ling
authors.initials: L
authors.lastname: Wang
authors.forename: Huilin
authors.initials: H
authors.lastname: Zhao
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000480:Alkynes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000577:Amides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D001798:Blood Proteins / Q000378:metabolism; D002460:Cell Line; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008168:Lung / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D010766:Phosphorylation; D011485:Protein Binding; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D042787:Receptor, TIE-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000480:Alkynes; D000577:Amides; D020533:Angiogenesis Inhibitors; D001798:Blood Proteins; D011743:Pyrimidines; D000255:Adenosine Triphosphate; D042787:Receptor, TIE-2