title: Identification of triazolopyridazinones as potent p38α inhibitors.
abstract: Structure-activity relationship (SAR) investigations of a novel class of triazolopyridazinone p38α mitogen activated protein kinase (MAPK) inhibitors are disclosed. From these studies, increased in vitro potency was observed for 2,6-disubstituted phenyl moieties and N-ethyl triazolopyridazinone cores due to key contacts with Leu108, Ala157 and Val38. Further investigation led to the identification of three compounds, 3g, 3j and 3m that are highly potent inhibitors of LPS-induced MAPKAP kinase 2 (MK2) phosphorylation in 50% human whole blood (hWB), and possess desirable in vivo pharmacokinetic and kinase selectivity profiles.
authors.affiliation: Department of Chemistry Research and Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA. brad.herberich@amgen.com
authors.forename: Brad
authors.initials: B
authors.lastname: Herberich
authors.forename: Claire
authors.initials: C
authors.lastname: Jackson
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Wurz
authors.forename: Liping H
authors.initials: LH
authors.lastname: Pettus
authors.forename: Lisa
authors.initials: L
authors.lastname: Sherman
authors.forename: Qiurong
authors.initials: Q
authors.lastname: Liu
authors.forename: Bradley
authors.initials: B
authors.lastname: Henkle
authors.forename: Christiaan J M
authors.initials: CJ
authors.lastname: Saris
authors.forename: Lu Min
authors.initials: LM
authors.lastname: Wong
authors.forename: Samer
authors.initials: S
authors.lastname: Chmait
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Lee
authors.forename: Christopher
authors.initials: C
authors.lastname: Mohr
authors.forename: Faye
authors.initials: F
authors.lastname: Hsieh
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Tasker
mesh_terms: D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D006801:Humans; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D014230:Triazoles; D048308:Mitogen-Activated Protein Kinase 14