Design, synthesis and preliminary evaluation of the anti-inflammatory of the specific selective targeting druggable enzymome cyclooxygenase-2 (COX-2) small molecule.
BACKGROUND
Development of a reliable and selective anti-inflammatory agent of cyclooxygenase-2 (COX-2), induced or up-regulated by inflammatory/injury stimulus such as IL-1β, TNF-α and LPS in the various types of organs, tissues and cells, with low side effects is a long-standing medicinal chemistry problem with significant social implications.


OBJECTIVE
To target druggable enzymome COX-2 by exploiting NSAIDs and genipin (GEP) in anti-inflammatory infection.


METHODS
The compound aspirin GEP ester (AGE) was designed by computer-assisted screening, synthesized in the esterification of the acylate derivative and the methylate derivative with Et3N, and evaluated with 20, 40 and 60 mg/kg from days 18 to 24 after immunization in collagen-induced arthritis (CIA) rats by the sequential enzymatic experiments, western-blot analysis and pathological observation methods.


RESULTS
AGE exhibited higher binding affinity with COX-1 and displayed the lowest estimated free energy with COX-2 than other ligands built by hanging NSAIDs with GEP, and was characterized by1H NMR,13C NMR and HRMS. AGE was competed against COX-2 with molecule-dependent potencies and selectivity (IC50: 0.36 mM; selectivity index: 275) in the sequential enzymatic experiments and decreased the expression of COX-2 in peripheral blood lymphocytes of CIA rats. AGE (40 and 60 mg/kg) could significantly relieve the secondary hind paw swelling and arthritis index, along with observing AGE attenuated histopathological changes of fibroblast like synovial tissue (FLST) and mesenteric lymph node lymphocytes (MLNL) in CIA rats.


CONCLUSIONS
AGE pharmacophore reported herein may be an effective strategy to develop a novel anti-inflammatory agent and potential inhibitor of COX-2.
a College of Pharmacy, Anhui University of Chinese Medicine , Key Laboratory of Modernized Chinese Medicine in Anhui Province , Hefei , Anhui , P.R. China.
Liang-Liang
LL
Sun
a College of Pharmacy, Anhui University of Chinese Medicine , Key Laboratory of Modernized Chinese Medicine in Anhui Province , Hefei , Anhui , P.R. China.
Hong
H
Wu
b Anhui Institute for Drug Control , Hefei , Anhui , P.R. China.
Ya-Zhong
YZ
Zhang
a College of Pharmacy, Anhui University of Chinese Medicine , Key Laboratory of Modernized Chinese Medicine in Anhui Province , Hefei , Anhui , P.R. China.
Rong
R
Wang
a College of Pharmacy, Anhui University of Chinese Medicine , Key Laboratory of Modernized Chinese Medicine in Anhui Province , Hefei , Anhui , P.R. China.
Wen-Yu
WY
Wang
a College of Pharmacy, Anhui University of Chinese Medicine , Key Laboratory of Modernized Chinese Medicine in Anhui Province , Hefei , Anhui , P.R. China.
Wei
W
Wang
a College of Pharmacy, Anhui University of Chinese Medicine , Key Laboratory of Modernized Chinese Medicine in Anhui Province , Hefei , Anhui , P.R. China.
Shu-Ping
SP
Li
a College of Pharmacy, Anhui University of Chinese Medicine , Key Laboratory of Modernized Chinese Medicine in Anhui Province , Hefei , Anhui , P.R. China.
Li
L
Dai
a College of Pharmacy, Anhui University of Chinese Medicine , Key Laboratory of Modernized Chinese Medicine in Anhui Province , Hefei , Anhui , P.R. China.
Zheng-Rong
ZR
Zhang
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000188:drug therapy; D001241:Aspirin / Q000737:chemistry / Q000494:pharmacology; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D039823:Iridoids / Q000494:pharmacology; D008297:Male; D062105:Molecular Docking Simulation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D000893:Anti-Inflammatory Agents; D052246:Cyclooxygenase 2 Inhibitors; D039823:Iridoids; C007834:genipin; D001241:Aspirin
Aspirin genipin ester; genipin; pharmacophore