Sodium N-(Methylsulfonyl)-N-(4-nitro- 2-phenoxyphenyl)sulfamate: A Water-Soluble Nimesulide Prodrug for Parenteral Use Simona Rapposelli,* ,† Maria Digiacomo, † Silvia Franchi, ‡ Sara Moretti, ‡ Mario Pinza, § Paola Sacerdote, ‡ and Aldo Balsamo † Dipartimento di Scienze Farmaceutiche, UniVersita ` di Pisa, Via Bonanno 6, 56100 Pisa, Italy, Dipartimento di Farmacologia, Chemioterapia e Tossicologia Medica, UniVersita ` degli Studi di Milano, Via VanVitelli 32, 20129 Milano, Italy, and Farma DeVelopment S.r.l., Via Amsterdam 132, 00144 Roma, Italy Received April 15, 2010; Revised Manuscript Received July 9, 2010; Accepted July 15, 2010 Abstract: Several nimesulide preparations (i.e., tablet form, gels) have been marketed, but no parenteral solution has achieved the market because of their low wettability and unsatisfactory chemical-physical properties required for parenteral use. In this paper we describe the synthesis of the nimesulide prodrug 1 and its anti-inﬂammatory and antihyperalgesic properties. Pharmacological studies, carried out to evaluate the in vivo anti-inﬂammatory and analgesic activities of compound 1 and nimesulide, showed that sodium sulfamate 1 is an effective nimesulide prodrug that can be administered by parenteral route, undergoing a satisfactory absorption and an extensive transformation into the active nimesulide compound. Moreover, the evaluation of the plasma concentrations of nimesulide after rat treatment with compound 1 showed an increased and dose-dependent release of nimesulide. In contrast, the plasma concentrations of nimesulide, after “native” drug administration, still remain substantially unchanged. These preliminary results prompt further investigations on this prodrug as a possible candidate for parenteral use. Keywords: Anti-inﬂammatory prodrug; analgesic prodrug; COX2 preferential drug; analgesia; nimesulide Introduction In the 1990s encouraging biochemical, pharmacological and clinical data prompted researchers to develop a new generation of anti-inﬂammatory drugs endowed of high selectivity toward COX2 isoenzyme. Although initially COX1 and COX2 were considered as the main isoenzymes responsible for the production of cytoprotective (COX1) and pro-inﬂammatory (COX2) prostaglandins, nowadays the physiological role of these isoenzymes is recognized as much more complex. Thus, there is a possibility that prostaglandins produced as a result of COX1 expression may also contribute to inﬂammation, pain and fever. Moreover, also prostaglan- dins produced by COX2 have been shown to play important physiological functions, including the regulation of bone resorption, 1 and the contribution to mucosal protection. 2,3 Recently, the detrimental role of COX2 enzyme in cardio- vascular homeostasis has been underlined. Brief periods of ischemia increase the myocardial resistance against a sub- * Correspondence and reprints. Mailing address: Universita ` di Pisa, Dipartimento di Scienze Farmaceutiche, Via Bonanno 6, 56100 Pisa, Italy. E-mail: simona.rapposelli@farm.unipi.it. Tel: +39- 050-2219582. Fax: +39-050-2219605. † Universita ` di Pisa. ‡ Universita ` degli Studi di Milano. § Farma Development S.r.l. (1) Onoe, Y.; Miyaura, K. T.; Nagai, Y.; Noguchi, K.; Chen, Q. R.; Seo, H.; Ohta, H.; Nozawa, S.; Kudo, I.; Suda, T. IL-13 and IL-4 inhibit bone resorption by suppressing cyclooxygenase-2-depend- ent prostaglandin synthesis in osteoblasts. J. Immunol. 1996, 156, 758. (2) Wallace, J. L. COX-2: a pivotal enzyme in mucosal protection and resolution of inﬂammation. Sci. World J. 2006, 6, 577. (3) Wallace, J. L.; Devchand, P. R. Emerging roles for cyclooxyge- nase-2 in gastrointestinal mucosal defense. Br. J. Pharmacol. 2005, 145, 275. brief articles 10.1021/mp1001137  2010 American Chemical Society VOL. 7, NO. 5, 1871–1876 MOLECULAR PHARMACEUTICS 1871 Published on Web 07/15/2010