Reducing ion channel activity in a series of 4-heterocyclic arylamide FMS inhibitors.
During efforts to improve the bioavailability of FMS kinase inhibitors 1 and 2, a series of saturated and aromatic 4-heterocycles of reduced basicity were prepared and evaluated in an attempt to also improve the cardiovascular safety profile over lead arylamide 1, which possessed ion channel activity. The resultant compounds retained excellent potency and exhibited diminished ion channel activity.
Wilson
Kenneth J
KJ
Johnson & Johnson Pharmaceutical Research & Development, Spring House, PA 19477, USA. kwilso10@its.jnj.com
Illig
Carl R
CR
Chen
Jinsheng
J
Wall
Mark J
MJ
Ballentine
Shelley K
SK
DesJarlais
Renee L
RL
Chen
Yanmin
Y
Schubert
Carsten
C
Donatelli
Robert
R
Petrounia
Ioanna
I
Crysler
Carl S
CS
Molloy
Christopher J
CJ
Chaikin
Margery A
MA
Manthey
Carl L
CL
Player
Mark R
MR
Tomczuk
Bruce E
BE
Meegalla
Sanath K
SK
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D010084:Oxidation-Reduction; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000577:Amides; D006571:Heterocyclic Compounds; D047428:Protein Kinase Inhibitors; D016186:Receptor, Macrophage Colony-Stimulating Factor