Synthesis and biological evaluation of N-difluoromethyl-1,2-dihydropyrid-2-one acetic acid regioisomers: Dual Inhibitors of cyclooxygenases and 5-lipoxygenase

doi:10.1016/j.bmcl.2010.02.040

Bioorganic & Medicinal Chemistry Letters

Volume 20, Issue 7, 1 April 2010, Pages 2168-2173

https://doi.org/10.1016/j.bmcl.2010.02.040 Get rights and content

Abstract

A new group of acetic acid (7a–c, R¹ = H), and propionic acid (7d–f, R¹ = Me), regioisomers wherein a N-difluoromethyl-1,2-dihydropyrid-2-one moiety is attached via its C-3, C-4, and C-5 position was synthesized. This group of compounds exhibited a more potent inhibition, and hence selectivity, for the cyclooxygenase-2 (COX-2) relative to the COX-1 isozyme. Attachment of the N-difluoromethyl-1,2-dihydropyrid-2-one ring system to an acetic acid, or propionic acid, moiety confers potent 5-LOX inhibitory activity, that is, absent in traditional arylacetic acid NSAIDs. 2-(1-Difluoromethyl-2-oxo-1,2-dihydropyridin-5-yl)acetic acid (7c) exhibited the best combination of dual COX-2 and 5-LOX inhibitory activities. Molecular modeling (docking) studies showed that the highly electronegative CHF₂ substituent present in 7c, that showed a modest selectivity for the COX-2 isozyme, is oriented within the secondary pocket (Val523) present in COX-2 similar to the sulfonamide (SO₂NH₂) COX-2 pharmacophore present in celecoxib, and that the N-difluoromethyl-1,2-dihydropyrid-2-one pharmacophore is oriented close to the region containing the LOX enzyme catalytic iron (His361, His366, and His545). Accordingly, the N-difluoromethyl-1,2-dihyrdopyrid-2-one moiety possesses properties suitable for the design of dual COX-2/5-LOX inhibitory drugs.

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Acknowledgments

We are grateful to the Canadian Institutes of Health Research (CIHR) (MOP-14712) for financial support of this research. Gang Yu was a recipient of a Jiangsu Government Abroad Study Scholarship, China.

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In this context, pyridone and pyridine ring systems comprise an important class of compounds known to exhibit various pharmacological properties including anti-inflammatory activity24,25. 2-Pyridone core and its tautomer, 2-hydroxypyridine, have been reported as a feature of several new NSAIDs26–28. For instance, the C-3, C-4 and C-5 regioisomers VI were evaluated toward COXs enzymes.
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Molecular modeling studies displayed that at COX −2 active site electronegative CHF2 group was oriented to the secondary pocket. The N-difluoromethyl-1,2-dihydropyrid-2-one was directed close to the catalytic iron region at LOX active site (Yu et al., 2010). Moreover, tolyl ring present in Celecoxib was replaced by N-hydroxypyridin-2(1H) one moiety which has the ability to chelate iron and inhibit 5-LOX enzyme.
Inflammatory mediators of the arachidonic acid cascade from cyclooxygenase (COX) and lipoxygenase (LOX) pathways are primarily responsible for many diseases in human beings. Chronic inflammation is associated with the pathogenesis and progression of cancer, arthritis, autoimmune, cardiovascular and neurological diseases. Traditional non-steroidal anti-inflammatory agents (tNSAIDs) inhibit cyclooxygenase pathway non-selectively and produce gastric mucosal damage due to COX-1 inhibition and allergic reactions and bronchospasm resulting from increased leukotriene levels. ‘Coxibs’ which are selective COX-2 inhibitors cause adverse cardiovascular events. Inhibition of any of these biosynthetic pathways could switch the metabolism to the other, which can lead to fatal side effects. Hence, there is undoubtedly an urgent need for new anti-inflammatory agents having dual mechanism that prevent release of both prostaglandins and leukotrienes. Though several molecules have been synthesized with this objective, their unfavourable toxicity profile prevented them from being used in clinics. Here, this integrative review attempts to identify the promising pharmacophore that serves as dual inhibitors of COX-2/5-LOX enzymes with improved safety profile. A better acquaintance of structural features that balance safety and efficacy of dual inhibitors would be a different approach to the process of understanding and interpreting the designing of novel anti-inflammatory agents.
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In general, the biosynthesis involves the conversion of arachidonic acid to prostaglandin G2 (PGH2), a reaction catalyzed by the sequential action of cyclooxygenase (COX) (Fig. 1). Most NSAIDs inhibit COX-1 and COX-2 isoforms.1–3 The constitutive COX-1 is responsible for the synthesis of cytoprotective prostaglandins in the gastrointestinal tract, and for the pro-aggregator thromboxane in blood platelets.4
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Synthesis and biological evaluation of N-difluoromethyl-1,2-dihydropyrid-2-one acetic acid regioisomers: Dual Inhibitors of cyclooxygenases and 5-lipoxygenase

Abstract

Graphical abstract

Section snippets

Acknowledgments

Eur. J. Med. Chem.

Trends Cardiovasc. Med.

Biochem. Pharmacol.

Eur. J. Med. Chem.

Bioorg. Med. Chem. Lett.

J. Med. Chem.

J. Am. Chem. Soc.

J. Org. Chem.

Bioorg. Med. Chem. Lett.

Tetrahedron

J. Biol. Chem.

Science

Ann. Clin. Lab. Sci.

Bioorg. Med. Chem. Lett.