title: Discovery of highly selective and potent p38 inhibitors based on a phthalazine scaffold.
abstract: Investigations into the structure-activity relationships (SAR) of a series of phthalazine-based inhibitors of p38 are described. These efforts originated from quinazoline 1 and through rational design led to the development of a series of orally bioavailable, potent, and selective inhibitors. Kinase selectivity was achieved by exploiting a collection of interactions with p38alpha including close contact to Ala157, occupation of the hydrophobic gatekeeper pocket, and a residue flip with Gly110. Substitutions on the phthalazine influenced the pharmacokinetic properties, of which compound 16 displayed the most desirable profile. Oral dosing (0.03 mg/kg) of 16 in rats 1 h prior to LPS challenge gave a >50% decrease in TNFalpha production.
authors.affiliation: Department of Medicinal Chemistry, Amgen, Inc., Thousand Oaks, California 91320-1799, USA. brad.herberich@amgen.com
authors.forename: Brad
authors.initials: B
authors.lastname: Herberich
authors.forename: Guo-Qiang
authors.initials: GQ
authors.lastname: Cao
authors.forename: Partha P
authors.initials: PP
authors.lastname: Chakrabarti
authors.forename: James R
authors.initials: JR
authors.lastname: Falsey
authors.forename: Liping
authors.initials: L
authors.lastname: Pettus
authors.forename: Robert M
authors.initials: RM
authors.lastname: Rzasa
authors.forename: Anthony B
authors.initials: AB
authors.lastname: Reed
authors.forename: Andreas
authors.initials: A
authors.lastname: Reichelt
authors.forename: Kelvin
authors.initials: K
authors.lastname: Sham
authors.forename: Maya
authors.initials: M
authors.lastname: Thaman
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Wurz
authors.forename: Shimin
authors.initials: S
authors.lastname: Xu
authors.forename: Dawei
authors.initials: D
authors.lastname: Zhang
authors.forename: Faye
authors.initials: F
authors.lastname: Hsieh
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Lee
authors.forename: Rashid
authors.initials: R
authors.lastname: Syed
authors.forename: Vivian
authors.initials: V
authors.lastname: Li
authors.forename: David
authors.initials: D
authors.lastname: Grosfeld
authors.forename: Matthew H
authors.initials: MH
authors.lastname: Plant
authors.forename: Bradley
authors.initials: B
authors.lastname: Henkle
authors.forename: Lisa
authors.initials: L
authors.lastname: Sherman
authors.forename: Scot
authors.initials: S
authors.lastname: Middleton
authors.forename: Lu Min
authors.initials: LM
authors.lastname: Wong
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Tasker
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D006801:Humans; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D010793:Phthalazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship
chemical_list: D010793:Phthalazines; D047428:Protein Kinase Inhibitors; D011804:Quinolines; C043388:phthalazine; C037219:quinoline; D048308:Mitogen-Activated Protein Kinase 14