ORIGINAL ARTICLEDesign, synthesis, molecular modeling, and biological evaluation of acrylamide derivatives as potent inhibitors of human dihydroorotate dehydrogenase for the treatment of rheumatoid arthritis☆
Under a Creative Commons license
open access
Graphical abstract
Dihydroorotate dehydrogenase (DHODH) is an attracting target for the treatment of immunological diseases. A series of acrylamide-based novel DHODH inhibitors as potential rheumatoid arthritis (RA) treatment agents were designed and synthesized, among which 54 is the most potent one with good pharmacokinetic profiles and favorable in vivo anti-arthritic effects.
KEY WORDS
DHODH
De novo pyrimidine biosynthesis
DHODH inhibitors
Acrylamide derivatives
Rheumatoid arthritis
Abbreviations
AML
acute myeloid leukemia
BPO
benzoyl peroxide
CIA
collagen-induced arthritis
DCE
1,2-dichloroethane
DCM
dichloromethane
DHODH
dihydroorotate dehydrogenase
DMAP
4-dimethylaminopyridine
DMARDs
disease-modifying antirheumatic drugs
DMF
N,N-dimethylformamide
DMSO
dimethyl sulfoxide
EA
ethyl acetate
FMN
flavin mononucleotide
HPLC
high performance liquid chromatography
HRMS
high-resolution mass spectrometry
IBD
inflammatory bowel disease
LAH
lithium aluminium hydride
LCMS
liquid chromatography mass spectrometry
MeOH
methanol
MS
multiple sclerosis
NBS
N-bromosuccinimide
NCS
N-chlorosuccinimide
NSAIDs
non-steroidal anti-inflammatory drugs
PDA
photodiode array detector
PE
petroleum ether
PhMe
toluene
PK
pharmacokinetic
RA
rheumatoid arthritis
SEL
systemic lupus erythematosus
TEA
triethylamine
TFA
trifluoroacetic acid
THF
tetrahydrofuran
TsCl
tosyl chloride
Cited by (0)
Peer review under responsibility of Institute of Materia Medica, Chinese Academy of Medical Sciences and Chinese Pharmaceutical Association.
- ☆
This paper is dedicated to Prof. Youyou Tu, the 2015 Nobel Prize laureate of Physiology or Medicine on the occasion of her 90th birthday.
- †
These authors made equal contributions to this work.
© 2021 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.