Design and synthesis of new water-soluble tetrazolide derivatives of celecoxib and rofecoxib as selective cyclooxygenase-2 (COX-2) inhibitors.

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Navidpour L, Amini M, Shafaroodi H, Abdi K, Ghahremani MH, Dehpour AR, Shafiee A

Design and synthesis of new water-soluble tetrazolide derivatives of celecoxib and rofecoxib as selective cyclooxygenase-2 (COX-2) inhibitors.

Bioorg Med Chem Lett. 2006 Sep 1;16(17):4483-7. Epub 2006 Jun 27.

PubMed ID

16806914 [ View in PubMed

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Abstract

In an attempt to prepare a new water-soluble, parenteral COX-2 inhibitor, rofecoxib (9) and celecoxib (13) analogues were designed and synthesized for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors with in vivo anti-inflammatory activity. In this experiment, respective SO(2)Me and SO(2)NH(2) hydrogen-bonding pharmacophores were replaced by a tetrazole ring. Molecular modeling (docking) studies showed that the tetrazole ring of these two analogues (9 and 13) was inserted deep into the secondary pocket of the human COX-2 binding site where it undergoes electrostatic interaction with Arg(513). The rofecoxib (9) and celecoxib (13) analogues exhibited a high in vitro selectivity (9, COX-1 IC(50) = 3.8 nM; COX-2 IC(50) = 1.8 nM; SI = 2.11; 13, COX-1 IC(50) = 4.1 nM; COX-2 IC(50) = 1.9 nM; SI = 2.16) relative to the reference drug celecoxib (COX-1 IC(50) = 3.7 nM; COX-2 IC(50) = .2 nM; SI=1.68) and also showed high aqueous solubility at pH higher than 7 and good anti-inflammatory activity in a carrageenan-induced rat paw edema assay. However, 9 and 13 had no significant damage on gastric mucosa.

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Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Celecoxib	Prostaglandin G/H synthase 2	IC 50 (nM)	2.2	N/A	N/A	Details