title: Enhancement of kinase selectivity in a potent class of arylamide FMS inhibitors.
abstract: Structure-activity relationship (SAR) studies on a highly potent series of arylamide FMS inhibitors were carried out with the aim of improving FMS kinase selectivity, particularly over KIT. Potent compound 17r (FMS IC50 0.7 nM, FMS cell IC50 6.1 nM) was discovered that had good PK properties and a greater than fivefold improvement in selectivity for FMS over KIT kinase in a cellular assay relative to the previously reported clinical candidate 4. This improved selectivity was manifested in vivo by no observed decrease in circulating reticulocytes, a measure of bone safety, at the highest studied dose. Compound 17r was highly active in a mouse pharmacodynamic model and demonstrated disease-modifying effects in a dose-dependent manner in a strep cell wall-induced arthritis model of rheumatoid arthritis in rats.
authors.affiliation: Janssen Pharmaceutical Research & Development LLC, Welsh & McKean Roads, Spring House, PA 19477, USA.
authors.forename: Carl R
authors.initials: CR
authors.lastname: Illig
authors.forename: Carl L
authors.initials: CL
authors.lastname: Manthey
authors.forename: Sanath K
authors.initials: SK
authors.lastname: Meegalla
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Wall
authors.forename: Jinsheng
authors.initials: J
authors.lastname: Chen
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Wilson
authors.forename: Renee L
authors.initials: RL
authors.lastname: DesJarlais
authors.forename: Shelley K
authors.initials: SK
authors.lastname: Ballentine
authors.forename: Carsten
authors.initials: C
authors.lastname: Schubert
authors.forename: Carl S
authors.initials: CS
authors.lastname: Crysler
authors.forename: Yanmin
authors.initials: Y
authors.lastname: Chen
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Molloy
authors.forename: Margery A
authors.initials: MA
authors.lastname: Chaikin
authors.forename: Robert R
authors.initials: RR
authors.lastname: Donatelli
authors.forename: Edward
authors.initials: E
authors.lastname: Yurkow
authors.forename: Zhao
authors.initials: Z
authors.lastname: Zhou
authors.forename: Mark R
authors.initials: MR
authors.lastname: Player
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Tomczuk
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D006571:Heterocyclic Compounds; D047428:Protein Kinase Inhibitors; D016186:Receptor, Macrophage Colony-Stimulating Factor
keywords: Anti-inflammatory; Colony-stimulating factor-1 receptor; FMS; Hypocellularity; KIT; Macrophage colony-stimulating factor; Rheumatoid arthritis