Anilino-monoindolylmaleimides as potent and selective JAK3 inhibitors.
We designed a series of anilino-indoylmaleimides based on structural elements from literature JAK3 inhibitors 3 and 4, and our lead 5. These new compounds were tested as inhibitors of JAKs 1, 2 and 3 and TYK2 for therapeutic intervention in rheumatoid arthritis (RA). Our requirements, based on current scientific rationale for optimum efficacy against RA with reduced side effects, was for potent, mixed JAK1 and 3 inhibition, and selectivity over JAK2. Our efforts yielded a potent JAK3 inhibitor 11d and its eutomer 11e. These compounds were highly selective for inhibition of JAK3 over JAK2 and TYK. The compounds displayed only modest JAK1 inhibition.
Fox Chase Chemical Diversity Center, Inc., 3805 Old Easton Road, Doylestown, PA 18902, United States.
Mark E
ME
McDonnell
Fox Chase Chemical Diversity Center, Inc., 3805 Old Easton Road, Doylestown, PA 18902, United States.
Haiyan
H
Bian
Fox Chase Chemical Diversity Center, Inc., 3805 Old Easton Road, Doylestown, PA 18902, United States. Electronic address: jwrobel@fc-cdci.com.
Jay
J
Wrobel
Fox Chase Chemical Diversity Center, Inc., 3805 Old Easton Road, Doylestown, PA 18902, United States.
Garry R
GR
Smith
Reaction Biology, Corp., One Great Valley Parkway, Suite 2, Malvern, PA 19355, United States.
Shuguang
S
Liang
Reaction Biology, Corp., One Great Valley Parkway, Suite 2, Malvern, PA 19355, United States.
Haiching
H
Ma
Fox Chase Chemical Diversity Center, Inc., 3805 Old Easton Road, Doylestown, PA 18902, United States.
Allen B
AB
Reitz
D000814:Aniline Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008301:Maleimides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000814:Aniline Compounds; D008301:Maleimides; D047428:Protein Kinase Inhibitors; C507933:JAK3 protein, human; D053616:Janus Kinase 3; C023650:aniline
Anilino-monoindolylmaleimide; JAK1 inhibitor; JAK2 selective inhibitor; JAK3 inhibitor; Rheumatoid arthritis