title: Structure-based optimization of a potent class of arylamide FMS inhibitors.
abstract: An anti-inflammatory 1,2,4-phenylenetriamine-containing series of FMS inhibitors with a potential to form reactive metabolites was transformed into a series with equivalent potency by incorporation of carbon-based replacement groups. Structure-based modeling provided the framework to efficiently effect this transformation and restore potencies to previous levels. This optimization removed a risk factor for potential idiosyncratic drug reactions.
authors.affiliation: Johnson & Johnson Pharmaceutical Research & Development, Welsh & McKean Roads, Spring House, PA 19477, USA.
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: Shelley K
authors.initials: SK
authors.lastname: Ballentine
authors.forename: Renee L
authors.initials: RL
authors.lastname: Desjarlais
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: Carl L
authors.initials: CL
authors.lastname: Manthey
authors.forename: Mark R
authors.initials: MR
authors.lastname: Player
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Tomczuk
authors.forename: Carl R
authors.initials: CR
authors.lastname: Illig
mesh_terms: D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D010655:Phenylenediamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D010655:Phenylenediamines; D016186:Receptor, Macrophage Colony-Stimulating Factor