Structure-based optimization of a potent class of arylamide FMS inhibitors.
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.
Meegalla
Sanath K
SK
Johnson & Johnson Pharmaceutical Research & Development, Welsh & McKean Roads, Spring House, PA 19477, USA.
Wall
Mark J
MJ
Chen
Jinsheng
J
Wilson
Kenneth J
KJ
Ballentine
Shelley K
SK
Desjarlais
Renee L
RL
Schubert
Carsten
C
Crysler
Carl S
CS
Chen
Yanmin
Y
Molloy
Christopher J
CJ
Chaikin
Margery A
MA
Manthey
Carl L
CL
Player
Mark R
MR
Tomczuk
Bruce E
BE
Illig
Carl R
CR
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
D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D010655:Phenylenediamines; D016186:Receptor, Macrophage Colony-Stimulating Factor