Design and synthesis of a novel mPGES-1 lead inhibitor guided by 3D-QSAR CoMFA

Mohd F. F., Mohd Aluwi and Rullah, Kamal and Koeberle, Andreas and Werz, Oliver and Nur Sakinah, Abdul Razak and Wei, Leong Sze and Fatimah, Salim and Nor Hadiani, Ismail and Ibrahim, Jantan and Wai, Lam K. (2019) Design and synthesis of a novel mPGES-1 lead inhibitor guided by 3D-QSAR CoMFA. Journal of Molecular Structure, 1196. pp. 844-850. ISSN 0022-2860. (Published)

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The search of novel mPGES-1 inhibitors has recently intensified probably due to the superior safety in comparison to existing anti-inflammatory drugs. Although two mPGES-1 inhibitors have entered clinical trials, none has yet reached the market. In this study, we performed modifications guided by 3D-QSAR CoMFA on 2, which is an unsymmetrical curcumin derivative with low binding affinity towards mPGES-1. To counter the PAINS properties predicted for 2, the diketone linker was replaced with a pyrazole ring. On the other hand, both prenyl and carboxylate ester groups were introduced to improve the activity. When tested in vitro, 11 suppressed PGE2 biosynthesis in activated macrophages and showed promising human mPGES-1 inhibition in microsomes of interleukin-1β-stimulated A549 cells. Altogether, 11 has been identified as a potential mPGES-1 inhibitor and could be a promising lead for a novel class of mPGES-1 inhibitors.

Item Type: Article
Additional Information: Indexed by Scopus
Uncontrolled Keywords: 3D-QSAR CoMFA; PGE2; mPGES-1; PAINS
Subjects: R Medicine > R Medicine (General)
R Medicine > RM Therapeutics. Pharmacology
R Medicine > RS Pharmacy and materia medica
Faculty/Division: Faculty of Industrial Sciences And Technology
Depositing User: Mrs Norsaini Abdul Samat
Date Deposited: 21 Nov 2019 01:53
Last Modified: 21 Nov 2019 01:53
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