Abstract:
:A novel class of indomethacin analogs were synthesized wherein a N-difluoromethyl-1,2-dihydropyrid-2-one moiety (5-LOX pharmacophore) was attached at its C-4 or C-5 position via either a CO (14a-b) or CH(2) (19a-b) linker to the indole N(1)-position. In this regard, replacement of the 4-chlorobenzoyl group present in indomethacin by N-difluoromethyl-1,2-dihydropyrid-2-one-4-(or 5-)carbonyl and N-difluoromethyl-1,2-dihydropyrid-2-one-4-yl(or 5-yl)methylene moieties furnished compounds showing no inhibitory activities against the COX-2/5-LOX enzymes (except for the weak but selective COX-2 inhibitor 19a, COX-2 IC(50)=31 μM), and moderate in vivo anti-inflammatory activities (except for the methylene compound 19a that was inactive). These structure-activity data indicate replacement of the 4-chlorobenzoyl group present in indomethacin by a N-difluoromethyl-1,2-dihydropyrid-2-one ring system connected by a CO or CH(2) linker is not a suitable approach for the design of dual COX-2/5-LOX inhibitory analogs of indomethacin.
journal_name
Bioorg Med Chem Lettjournal_title
Bioorganic & medicinal chemistry lettersauthors
Chowdhury MA,Huang Z,Abdellatif KR,Dong Y,Yu G,Velázquez CA,Knaus EEdoi
10.1016/j.bmcl.2010.07.132subject
Has Abstractpub_date
2010-10-01 00:00:00pages
5776-80issue
19eissn
0960-894Xissn
1464-3405pii
S0960-894X(10)01101-7journal_volume
20pub_type
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