title: Synthesis, structural analysis, and SAR studies of triazine derivatives as potent, selective Tie-2 inhibitors.
abstract: A novel class of selective Tie-2 inhibitors was derived from a multi-kinase inhibitor 1. By reversing the amide connectivity and incorporating aminotriazine or aminopyridine hinge-binding moieties, excellent Tie-2 potency and KDR selectivity could be achieved with 3-substituted terminal aryl rings. X-ray co-crystal structure analysis aided inhibitor design. This series was evaluated on the basis of potency, selectivity, and rat pharmacokinetic parameters.
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., One Kendall Square, Building 1000, Cambridge, MA 02139, 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: 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: 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: Rebecca E
authors.initials: RE
authors.lastname: Johnson
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: Ling
authors.initials: L
authors.lastname: Wang
authors.forename: Huilin
authors.initials: H
authors.lastname: Zhao
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D015195:Drug Design; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D042787:Receptor, TIE-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship; D014227:Triazines / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D014227:Triazines; D042787:Receptor, TIE-2