Structure-based drug design of RN486, a potent and selective Bruton's tyrosine kinase (BTK) inhibitor, for the treatment of rheumatoid arthritis.
Structure-based drug design was used to guide the optimization of a series of selective BTK inhibitors as potential treatments for Rheumatoid arthritis. Highlights include the introduction of a benzyl alcohol group and a fluorine substitution, each of which resulted in over 10-fold increase in activity. Concurrent optimization of drug-like properties led to compound 1 (RN486) ( J. Pharmacol. Exp. Ther. 2012 , 341 , 90 ), which was selected for advanced preclinical characterization based on its favorable properties.
pRED, Pharma Research & Early Development, Small Molecule Research, Discovery Chemistry, Hoffmann-La Roche Inc. , 3431 Hillview Avenue, Palo Alto, California 94304, United States.
Yan
Y
Lou
Xiaochun
X
Han
Andreas
A
Kuglstatter
Rama K
RK
Kondru
Zachary K
ZK
Sweeney
Michael
M
Soth
Joel
J
McIntosh
Renee
R
Litman
Judy
J
Suh
Buelent
B
Kocer
Dana
D
Davis
Jaehyeon
J
Park
Sandra
S
Frauchiger
Nolan
N
Dewdney
Hasim
H
Zecic
Joshua P
JP
Taygerly
Keshab
K
Sarma
Junbae
J
Hong
Ronald J
RJ
Hill
Tobias
T
Gabriel
David M
DM
Goldstein
Timothy D
TD
Owens
D000077329:Agammaglobulinaemia Tyrosine Kinase; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
D007546:Isoquinolines; C000588993:RN486; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human