title: Evolution of a highly selective and potent 2-(pyridin-2-yl)-1,3,5-triazine Tie-2 kinase inhibitor.
abstract: Inhibition of angiogenesis is a promising and clinically validated approach for limiting tumor growth and survival. The receptor tyrosine kinase Tie-2 is expressed almost exclusively in the vascular endothelium and is required for developmental angiogenesis and vessel maturation. However, the significance of Tie-2 signaling in tumor angiogenesis is not well understood. In order to evaluate the therapeutic utility of inhibiting Tie-2 signaling, we developed a series of potent and orally bioavailable small molecule Tie-2 kinase inhibitors with selectivity over other kinases, especially those that are believed to be important for tumor angiogenesis. Our earlier work provided pyridinyl pyrimidine 6 as a potent, nonselective Tie-2 inhibitor that was designed on the basis of X-ray cocrystal structures of KDR inhibitors 34 (triazine) and 35 (nicotinamide). Lead optimization resulted in pyridinyl triazine 63, which exhibited >30-fold selectivity over a panel of kinases, good oral exposure, and in vivo inhibition of Tie-2 phosphorylation.
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., One Kendall Square, Building 1000, Cambridge, Massachusetts 02139-1581, USA. bhodous@amgen.com
authors.forename: Brian L
authors.initials: BL
authors.lastname: Hodous
authors.forename: Stephanie D
authors.initials: SD
authors.lastname: Geuns-Meyer
authors.forename: Paul E
authors.initials: PE
authors.lastname: Hughes
authors.forename: Brian K
authors.initials: BK
authors.lastname: Albrecht
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: Victor J
authors.initials: VJ
authors.lastname: Cee
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: 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: 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: Paul
authors.initials: P
authors.lastname: Rose
authors.forename: Paul
authors.initials: P
authors.lastname: Tempest
authors.forename: Ling
authors.initials: L
authors.lastname: Wang
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Whittington
authors.forename: Huilin
authors.initials: H
authors.lastname: Zhao
mesh_terms: D000284:Administration, Oral; D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001665:Binding Sites; D001798:Blood Proteins / Q000378:metabolism; D018360:Crystallography, X-Ray; D005260:Female; D006801:Humans; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D010766:Phosphorylation; D011485:Protein Binding; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D042787:Receptor, TIE-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors
chemical_list: D020533:Angiogenesis Inhibitors; D001549:Benzamides; D001798:Blood Proteins; C518307:N-(2-((3-(dimethylamino)propyl)(methyl)amino)-5-(trifluoromethyl)phenyl)-2-fluoro-5-(3-(4-(methylamino)-1,3,5-triazin-2-yl)pyridin-2-yloxy)benzamide; D011725:Pyridines; D014227:Triazines; D042787:Receptor, TIE-2; D040301:Vascular Endothelial Growth Factor Receptor-2