Therapeutic Potential of Sulfamides as Enzyme Inhibitors Jean-Yves Winum, 1 Andrea Scozzafava, 2 Jean-Louis Montero, 1 Claudiu T. Supuran 2 1 Universite ´ Montpellier II, Laboratoire de Chimie Biomole ´ culaire, UMR 5032, Ecole Nationale Supe ´rieure de Chimie de Montpellier, 8 rue de l’Ecole Normale, 34296 Montpellier Cedex, France 2 Dipartimento di Chimica, Universita ` degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, I-50019 Sesto Fiorentino (Firenze), Italy Published online 18 May 2006 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/med.20068 ! Abstract: Sulfamide, a quite simple molecule incorporating the sulfonamide functionality, widely used by medicinal chemists for the design of a host of biologically active derivatives with pharmacological applications, may give rise to at least five types of derivatives, by substituting one to four hydrogen atoms present in it, which show specific biological activities. Recently, some of these compounds started to be exploited for the design of many types of therapeutic agents. Among the enzymes for which sulfamide-based inhibitors were designed, are the carbonic anhydrases (CAs), a large number of proteases belonging to the aspartic protease (HIV-1 protease, g-secretase), serine protease (elastase, chymase, tryptase, and thrombin among others), and metalloprotease (carboxypeptidase A (CPA) and matrix metalloproteinases (MMP)) families. Some steroid sulfatase (STS) and protein tyrosine phosphatase inhibitors belonging to the sulfamide class of derivatives have also been reported. In all these compounds, many of which show low nanomolar affinity for the target enzymes for which they have been designed, the free or substituted sulfamide moiety plays important roles for the binding of the inhibitor to the active site cavity, either by directly coordinating to a metal ion found in some metalloenzymes (CAs, CPA, STS), usually by means of one of the nitrogen atoms present in the sulfamide motif, or as in the case of the cyclic sulfamides acting as HIV protease inhibitors, interacting with the catalytically critical aspartic acid residues of the active site by means of an oxygen atom belonging to the HN–SO 2 –NH motif, which substitutes a catalytically essential water molecule. In other cases, the sulfamide moiety is important for inducing desired physico-chemical properties to the drug-like compounds incorporating it, such as enhanced water solubility, better bioavailability, etc., because of the intrinsic properties of this highly polarized moiety when attached to an organic scaffold. This interesting motif is thus of great value for the design of pharmacological agents with a lot of applications. ß 2006 Wiley Periodicals, Inc. Med Res Rev, 26, No. 6, 767–792, 2006 Contract grant sponsor: 6th Framework of Programme of the European Union (EUROXYproject). Correspondence to: Dr. Jean-Yves Winum and Dr ClaudiuT. Supuran,Dipartimento di Chimica,University of Florence,Laboratorio di Chimica Bioinorganica, Via della Lastruccia, 3, Rm.188, Polo Scientifico, 50019-Sesto Fiorentino (Firenze), Italy. E-mail: winumj@univ-montp2.fr; claudiu.supuran@unifi.it Medicinal Research Reviews, Vol. 26, No. 6, 767^792, 2006 ß 2006 Wiley Periodicals, Inc.