Design and synthesis of new rofecoxib analogs as selective cyclooxygenase-2 (COX-2) inhibitors: replacement of the methanesulfonyl pharmacophore by a N-acetylsulfonamido bioisostere.
OBJECTIVE
A group of 3,4-diaryl- 2(5H)furanones were synthesized to determine whether a N-acetylsulfonamido (SO2NHCOCH3) moiety could be used as a bioisosteric replacement for the traditional sulfonamide (SO2NH2) and methanesulfonyl (SO2CH3) COX-2 pharmacophores.


METHODS
In vitro COX-1 and COX-2 isozyme inhibition studies were carried out to acquire structure activity relationship data with respect to the point of attachment of the Nacetylsulfonamide moiety at the para and metapositions of the C-4 phenyl ring in conjunction with a variety of substituents (H, F, Cl, Me, OMe) at the para position of the C-3 phenyl ring.


RESULTS
COX-1 and COX-2 inhibition studies showed that all compounds were selective inhibitors of COX-2 since no inhibition of COX-1 was observed at a concentration of 100 microM. The relative COX-2 potency, and COX-2 selectivity index, profiles for the C-4 para acetamidophenyl compounds, with respect to the C-3 phenyl parasubstituent was H > F > Cl. The point of attachment of the SO2NHCOCH3 substituent on the C-4 phenyl ring was a determinant of COX-2 potency, and COX-2 selectivity, where the relative activity profile was para acetylsulfonamido > meta acetylsulfonamido. 4-[4-(NAcetylsulfonamido) phenyl]-3-phenyl-2(5H)furanone was identified as a more potent (IC50 = 0.32 microM), and selective (S.I. > 313), COX-2 inhibitor than the parent reference compound rofecoxib (IC50 = 0.43 microM, S.I. > 232).


CONCLUSIONS
The SO2NHCOCH3 moiety i) is a novel COX-2 pharmacophore that also has the potential to serve as a prodrug moiety to the traditional SO2NH2 COX-2 pharmacophore, and ii) it could serve as a useful COX-2 pharmacophore to study the structure-function relationship of the COX-2 isozyme in view of its potential to acetylate the NH2 moiety of amino acid residues such as Gln192 or Arg513 that line the pocket of the secondary COX-2 binding site.
Zarghi
Afshin
A
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.
Rao
P N Praveen
PN
Knaus
Edward E
EE
D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D005663:Furans / Q000138:chemical synthesis* / Q000494:pharmacology; D007783:Lactones; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D013450:Sulfones
D052246:Cyclooxygenase 2 Inhibitors; D005663:Furans; D007783:Lactones; D013450:Sulfones; C116926:rofecoxib; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2