Advanced search
Publication Cover
Expert Opinion on Therapeutic Patents Volume 16, 2006 - Issue 1
Submit an article Journal homepage
261
Views
66
CrossRef citations to date
0
Altmetric
Review

The sulfamide motif in the design of enzyme inhibitors

Jean-Yves Winum Assistant Professor, Université Montpellier II, Laboratoire de Chimie Biomoléculaire, UMR 5032, Ecole Nationale Supérieure de Chimie de Montpellier, 8 rue de l’Ecole Normale, 34296 Montpellier Cedex, France. [email protected]
,
Andrea Scozzafava Professor, Università degli Studi di Firenze, Dipartimento di Chimica, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, I-50019 Sesto Fiorentino (Firenze), Italy
,
Jean-Louis Montero Professor, Université Montpellier II, Laboratoire de Chimie Biomoléculaire, UMR 5032, Ecole Nationale Supérieure de Chimie de Montpellier, 8 rue de l’Ecole Normale, 34296 Montpellier Cedex, France
&
Claudiu T Supuran Professor, Università degli Studi di Firenze, Dipartimento di Chimica, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, I-50019 Sesto Fiorentino (Firenze), Italy. [email protected]
Pages 27-47 | Published online: 22 Dec 2005

Bibliography

  • SUPURAN CT, SCOZZAFAVA A, CASINI A: Carbonic anhydrase inhibitors. Med. Res. Rev. (2003) 23:146-189.
  • SUPURAN CT, SCOZZAFAVA A: Applications of carbonic anhydrase inhibitors and activators in therapy. Expert Opin. Ther. Patents (2002) 12:217-242.
  • SUPURAN CT, SCOZZAFAVA A: Carbonic anhydrase inhibitors and their therapeutic potential. Expert Opin. Ther. Patents (2000) 10:575-600.
  • SCOZZAFAVA A, OWA T, MASTROLORENZO A, SUPURAN CT: Anticancer and antiviral sulfonamides. Curr. Med. Chem. (2003) 10:925-953.
  • SCOZZAFAVA A, MASTROLORENZO A, SUPURAN CT: Modulation of carbonic anhydrase activity and its applications in therapy. Expert Opin. Ther. Pat. (2004) 14:667-702.
  • SUPURAN CT, SCOZZAFAVA A, CASINI A: Development of sulfonamide carbonic anhydrase inhibitors (CAIs). In: Carbonic Anhydrase, Its Inhibitors and Activators. Supuran CT, Scozzafava A, Conway J (Eds), CRC Press, Boca Raton, FL, USA (2004):67-147.
  • WINUM JY, SCOZZAFAVA A, MONTERO JL, SUPURAN CT: Sulfamate and their therapeutic potential. Med. Res. Rev. (2005) 25:186-228.
  • ABBATE F, SUPURAN CT, SCOZZAFAVA A, ORIOLI P, STUBBS MT, KLEBE G: Nonaromatic sulfonamide group as an ideal anchor for potent human carbonic anhydrase inhibitors: role of hydrogen-bonding networks in ligand binding and drug design. J. Med. Chem. (2002) 45:3583-3587.
  • WINUM JY, SCOZZAFAVA A, MONTERO JL, SUPURAN CT: Therapeutic applications of sulfamates. Expert Opin. Ther. Patents (2004) 14:1273-1308.
  • SUPURAN CT, SCOZZAFAVA A, CONWAY J (Eds): Carbonic Anhydrase – Its Inhibitors and Activators. CRC Press, Boca Raton, FL, USA (2004):1-363.
  • PASTOREKOVA S, PARKKILA S, PASTOREK J, SUPURAN CT: Carbonic anhydrases: current state of the art, therapeutic applications and future prospects. J. Enz. Inhib. Med. Chem. (2004) 19:199-229.
  • SUPURAN CT, SCOZZAFAVA A: Carbonic anhydrase inhibitors. Curr. Med. Chem. Imm. Endoc. Metab. Agents (2001) 1:61-97.
  • SUPURAN CT: Carbonic anhydrase inhibitors in the treatment and prophylaxis of obesity. Expert Opin. Ther. Patents (2003) 13:1545-1550.
  • SUPURAN CT: Indisulam: an anticancer sulfonamide in clinical development. Expert Opin. Investig. Drugs (2003) 12:283-287.
  • PASTOREKOVA S, PASTOREK J: Cancer-related carbonic anhydrase isozymes and their inhibition. In: Carbonic Anhydrase – Its Inhibitors and Activators. Supuran CT, Scozzafava A, Conway J (Eds), CRC Press, Boca Raton, FL, USA (2004):253-280.
  • HILVO M, TOLVANEN M, CLARK A et al.: Characterization of CA XV, a new GPI-anchored form of carbonic anhydrase. Biochem. J. (2005) 392:83-92.
  • BRIGANTI F, MANGANI S, ORIOLI P, SCOZZAFAVA A, VERNAGLIONE G, SUPURAN CT: Carbonic anhydrase activators: X-ray crystallographic and spectroscopic investigations for the interaction of isozymes I and II with histamine. Biochemistry (1997) 36:10384-10392.
  • MENCHISE V, DE SIMONE G, ALTERIO V et al.: Carbonic anhydrase inhibitors: stacking with Phe131 determines active site binding region of inhibitors as exemplified by the X-ray crystal structure of a membrane-impermeant antitumor sulfonamide complexed with isozyme II. J. Med. Chem. (2005) 48:5721-5727.
  • DE SIMONE G, DI FIORE A, MENCHISE V et al.: Carbonic anhydrase inhibitors. Zonisamide is an effective inhibitor of the cytosolic isozyme II and mitochondrial isozyme V: solution and X-ray crystallographic studies. Bioorg. Med. Chem. Lett. (2005) 15:2315-2320.
  • DI FIORE A, DE SIMONE G, MENCHISE V et al.: Carbonic anhydrase inhibitors: X-ray crystal structure of a benzenesulfonamide strong CA II and CA IX inhibitor bearing a pentafluorophenylaminothioureido tail in complex with isozyme II. Bioorg. Med. Chem. Lett. (2005) 15:1937-1942.
  • CASINI A, ANTEL J, ABBATE F et al.: Carbonic anhydrase inhibitors: SAR and X-ray crystallographic study for the interaction of sugar sulfamates/sulfamides with isozymes I, II and IV. Bioorg. Med. Chem. Lett. (2003) 13:841-845.
  • SVASTOVA E, HULIKOVA A, RAFAJOVA M et al.: Hypoxia activates the capacity of tumor-associated carbonic anhydrase IX to acidify extracellular pH. FEBS Lett. (2004) 577:439-445.
  • BRIGANTI F, PIERATTELLI R, SCOZZAFAVA A, SUPURAN CT: Carbonic anhydrase inhibitors. Part 37. Novel classes of carbonic anhydrase inhibitors and their interaction with the native and cobalt-substituted enzyme: kinetic and spectroscopic investigations. Eur. J. Med. Chem. (1996) 31:1001-1010.
  • SCOZZAFAVA A, BANCIU MD, POPESCU A, SUPURAN CT: Carbonic anhydrase inhibitors. Inhibition of isozymes I, II and IV by sulfamide and sulfamic acid derivatives. J. Enz. Inhib. (2000) 15:443-453.
  • CASINI A, WINUM J-Y, MONTERO J-L, SCOZZAFAVA A, SUPURAN CT: Carbonic anhydrase inhibitors: inhibition of cytosolic isozymes I and II with sulfamide derivatives. Bioorg. Med. Chem. Lett. (2003) 13:837-840.
  • WINUM J-Y, INNOCENTI A, NASR J et al.: Carbonic anhydrase inhibitors: Synthesis and inhibition of cytosolic/tumor-associated carbonic anhydrase isozymes I, II, IX and XII with N-hydroxy-sulfamides – a new zinc binding function in the design of inhibitors. Bioorg. Med. Chem. Lett. (2005) 15:2353-2358.
  • WINUM J-Y, CECCHI A, MONTERO J-L, INNOCENTI A, SCOZZAFAVA A, SUPURAN CT: Carbonic anhydrase inhibitors. Synthesis and inhibition of cytosolic/tumor-associated carbonic anhydrase isozymes I, II and IX with boron-containing sulfonamides, sulfamides and sulfamates: towards agents for boron neutron capture therapy of hypoxic tumors. Bioorg. Med. Chem. Lett. (2005) 15:3302-3306.
  • LEUNG D, ABBENANTE G, FAIRLIE DP: Protease inhibitors: current status and future prospects. J. Med. Chem. (2000) 43:305-341.
  • SMITH HJ, SIMONS C: Protease and Peptidase Inhibition – Recent Potential Target for Drug Development. Taylor & Francis, London and New York (2002):1-412
  • NIESTROJ AJ, DEMUTH HU: Proteases. In: Enzymes and Their Inhibition – Drug Development. Smith J, Simons C (Eds), CRC Press, Boca Raton, FL, USA (2005):88-117.
  • SUPURAN CT, CASINI A, SCOZZAFAVA A: Protease inhibitors of the sulfonamide type: anticancer, anti-inflammatory and antiviral agents. Med. Res. Rev. (2003) 23:535-558.
  • SUPURAN CT, SCOZZAFAVA A, CLARE BW: Bacterial protease inhibitors. Med. Res. Rev. (2002) 22:329-372.
  • OGDEN RC, FLEXNER CW (Eds): Protease Inhibitors in AIDS Therapy. Marcel Dekker, New York, Basel, USA (2001):1-310.
  • ERICKSON JW: HIV-1 protease as a target for AIDS therapy. In: Protease Inhibitors in AIDS Therapy. Ogden RC, Flexner CW (Eds) Marcel Dekker, New York, USA (2001):1-25.
  • SCHECHTER I, BERGER A: On the size of the active site in proteases. I. Papain. Biochem. Biophys. Res. Commun. (1967) 27:157-162.
  • BARBARO G, SCOZZAFAVA A, MASTROLORENZO A, SUPURAN CT: Highly active antiretroviral therapy: current state of the art, new agents and their pharmacological interactions useful for improving therapeutic outcome. Curr. Pharm. Des. (2005) 11:1805-1843.
  • DUNCAN IB, REDSHAW S: Discovery and early development of saquinavir. In: Protease Inhibitors in AIDS Therapy. Ogden RC, Flexner CW (Eds), Marcel Dekker, New York, USA (2001):27-47.
  • KEMPF DJ: Discovery and early development of ritonavir and ABT-378. In: Protease Inhibitors in AIDS Therapy. Ogden RC, Flexner CW (Eds), Marcel Dekker, New York, USA (2001):49-64.
  • DORSEY BD, VACCA JP: Discovery and early development of indinavir. In: Protease Inhibitors in AIDS therapy. Ogden RC, Flexner CW (Eds), Marcel Dekker, New York, USA (2001):65-83.
  • REICH SH:. Discovery and early development of nelfinavir (Viracept). In: Protease Inhibitors in AIDS Therapy. Ogden RC, Flexner CW (Eds), Marcel Dekker, New York, USA (2001):85-99.
  • TUNG RD, LIVINGSTON DJ, RAO BG et al.: Design and synthesis of amprenavir, a novel HIV protease inhibitor. In: Protease inhibitors in AIDS therapy. Ogden RC, Flexner CW (Eds), Marcel Dekker, New York, USA (2001):101-118.
  • HULTEN J, BONHAM NM, NILLROTH U et al.: Cyclic HIV-1 protease inhibitors derived from mannitol: synthesis, inhibitory potencies, and computational predictions of binding affinities. J. Med. Chem. (1997) 40:885-897.
  • BACKBRO K, LOWGREN S, OSTERLUND K et al.: Unexpected binding mode of a cyclic sulfamide HIV-1 protease inhibitor. J. Med. Chem. (1997) 40:898-902.
  • HULTEN J, ANDERSSON HO, SCHAAL W et al.: Inhibitors of the C(2)-symmetric HIV-1 protease: nonsymmetric binding of a symmetric cyclic sulfamide with ketoxime groups in the P2/P2′ side chains. J. Med. Chem. (1999) 42:4054-4061.
  • ALA PJ, CHANG CH: HIV aspartate proteinase: resistance to inhibitors. In: Proteinase and Peptidase Inhibition: Recent Potential Targets for Drug Development. Smith HJ, Simons C. (Eds), Taylor & Francis Publishing House, London and New York (2002):367-382.
  • SCHMIDT B: Aspartic proteases involved in Alzheimer’s disease. ChemBioChem (2003) 4:366-378.
  • POLLACK SJ, LEWIS H: Secretase inhibitors for Alzheimer’s disease: challenges of a promiscuous protease. Curr. Opin. Investig. Drugs (2005) 6:35-47.
  • TOMITA T, IWATSUBO T: The inhibition of γ-secretase as a therapeutic approach to Alzheimer’s disease. Drug News Perspect. (2004) 17:321-325.
  • TSAI JY: WOLFE MS, XIA W: The search for γ-secretase and development of inhibitors. Curr. Med. Chem. (2002) 9:1087-1106.
  • ROBERTS SB: γ-Secretase inhibitors and Alzheimer’s disease. Adv. Drug Deliv. Rev. (2002) 54:1579-1588.
  • WOLFE MS: Secretase targets for Alzheimer’s disease: identification and therapeutic potential. J. Med. Chem. (2001) 44:2039-2060.
  • SPAREY T, BEHER D, BEST J et al.: Cyclic sulfamide γ-secretase inhibitors. Bioorg. Med. Chem. Lett. (2005) 15:4212-4216.
  • CHRISTIANSON DW, LIPSCOMB NW: Carboxypeptidase A. Acc. Chem. Res. (1989) 22:62-69.
  • LIPSCOMB NW, STRATER N: Recent advances in zinc enzymology. Chem. Rev. (1996) 96:2375-2433.
  • KIM DH: Chemistry-based design of inhibitors for carboxypeptidases A. Curr. Top. Med. Chem. (2004) 4:1217-1226.
  • PARK JD, KIM DH, KIM SJ, WOO JR, RYU SE: Sulfamide-based inhibitors for carboxypeptidase A. Novel type transition state analogue inhibitors for zinc proteases. J. Med. Chem. (2002) 45:5295-5302.
  • PARK JD, KIM DH: Sulfamide derivatives as transition state analogue inhibitors for carboxypeptidase A. Bioorg. Med. Chem. (2004) 12:2349-2356.
  • SUPURAN CT, SCOZZAFAVA A: Metalloproteinase – collagenase inhibitors examples. In: Enzymes and Their Inhibition – Drug Development. Smith HJ, Simons C (Eds) CRC Press, Boca Raton, FL, USA (2005):292-300.
  • SUPURAN CT, SCOZZAFAVA A: Matrix metalloproteinase (MMPs). In: Proteinase and Peptidase Inhibition – Recent Potential Target for Drug Development. Smith HJ, Simons C (Eds), Taylor & Francis, London (2002):35-61.
  • KONTOGIORGIS GA, PAPAIOANNOU P, HADJIPAVLOU LITINA DJ: Matrix metalloproteinase inhibitors: a review on pharmacophore mapping and (Q)SARs results. Curr. Med. Chem. (2005) 12:339-355.
  • MATTER H, SCHUDOK M: Recent advances in the design of matrix metalloprotease inhibitors. Curr. Opin. Drug. Discov. Devel. (2004) 7:513-535.
  • WHITTAKER M, FLOYD CD, BROWN P, GEARING AJ: Design and therapeutic application of matrix metalloproteinase inhibitors. Chem. Rev. (1999) 99:2735-2776.
  • DOHERTY TM, ASOTRA K, PEI D et al.: Therapeutic developments in matrix metalloproteinase inhibition. Expert Opin. Ther. Patents (2002) 12:665-707.
  • ILIES MA, SUPURAN CT, SCOZZAFAVA A: Therapeutic applications of serine protease inhibitors. Expert Opin. Ther. Patents (2002) 12:1181-1214.
  • ZHONG J, GROUTAS WC: Recent developments in the design of mechanism-based and alternate substrate inhibitors of serine proteases. Curr. Top. Med. Chem. (2004) 4:1203-1216.
  • CASINI A, SCOZZAFAVA A, SUPURAN CT: Sulfonamide derivatives with protease inhibitory action as anticancer, antiinflammatory and antiviral agents. Expert Opin. Ther. Pat. (2002) 12:1307-1327.
  • GROUTAS WC, EPP JB, KUANG R et al.: 1,2,5-Thiadiazolidin-3-one 1,1-dioxide: a powerful scaffold for probing the S′ subsites of (chymo)trypsin-like serine protease. Arch. Biochem. Biophys. (2001) 385:162-169.
  • GROUTAS WC, HE S, KUANG R, RUAN S, TU J, CHAN HK: Inhibition of serine protease by functionalized sulphonamide coupled to the 1,2,5-thiadiazolidin-3-one 1,1-dioxide scaffold. Bioorg. Med. Chem. (2001) 9:1543-1548.
  • LAI Z, GAN X, WEI L et al.: Potent inhibition of human leukocyte elastase by 1,2,5-thiadiazolidin-3-one 1,1-dioxide-based sulfonamide derivatives. Arch. Biochem. Biophys. (2004) 429:191-197.
  • KUANG R, VENKATARAMAN R, RUAN S, GROUTAS WC: Use of the 1,2,5-thiadiazolidin-3-one 1,1-dioxide scaffolds in the design of potent inhibitors of serine proteinase. Bioorg. Med. Chem. Lett. (1998) 8:539-544.
  • GROUTAS WC, KUANG R, RUAN S, EPP JB, VENKATARAMAN R, TRUONG TM: Potent and specific inhibition of human leukocyte elastase, cathepsin G and proteinase 3 by sulfone derivatives employing the 1,2,5-thiadiazolidin-3-one 1,1-dioxide scaffold. Bioorg. Med. Chem. (1998) 6:661-671.
  • KUANG R, EPP JB, RUAN S et al.: Utilization of the 1,2,5-thiadiazolidin-3-one 1,1-dioxide scaffold in the design of potent inhibitors of serine proteases: SAR studies using carboxylate. Bioorg. Med. Chem. (2000) 8:1005-1016.
  • HE S, KUANG R, VENKATARAMAN R et al.: Potent inhibition of serine protease by heterocyclic sulfide derivatives of 1,2,5-thiadiazolidin-3-one 1,1-dioxide. Bioorg. Med. Chem. (2000) 8:1713-1717.
  • ZHONG J, GAN X, ALLISTON KR, GROUTAS W: Design, synthesis and in vitro evaluation of inhibitors of human leukocyte elastase based on a functionalized cyclic sulfamide scaffold. Bioorg. Med. Chem. Lett. (2004) 12:589-593.
  • ZHONG J, GAN X, ALLISTON KR et al.: Potential protease inhibitors based on functionnalized cyclic sulfamide scaffold. J. Comb. Chem. (2004) 6:556-563.
  • TAKAI S, JIN D, MURAMATSU M, OKAMOTO Y, MIYAZAKI M: Therapeutic applications of chymase inhibitors in cardiovascular diseases and fibrosis. Eur. J. Pharmacol. (2004) 501:1-8.
  • DOGGRELL SH, WANSTALL JC: Vascular chymase: pathophysiological role and therapeutic potential of inhibition. Cardiovascular Res. (2004) 61:653-662.
  • TAKAI S, JIN D, MURAMATSU M, MIYAZAKI M: Chymase as a novel target for the prevention of vascular diseases. Trends Pharm. Sci. (2004) 25:519-522.
  • GROUTAS WC, SCHECHTER NM, HE S, YU H, HUANG P, TU J: Human chymase inhibitors based on the 1,2,5-thiadiazolidin-3-one 1,1-dioxide scaffold. Bioorg. Med. Chem. Lett. (1999) 9:2199-2204.
  • CAIRNS JA: Inhibitors of mast cell tryptase β as therapeutics for the treatment of asthma and inflammation disorders. Pulmon. Pharmacol. Ther. (2005) 18:55-66.
  • WONG T, GROUTAS CS, MOHAN S et al.: 1,2,5-Thiadiazolidin-3-one 1,1-dioxide-based heterocyclic sulfides are potent inhibitors of human tryptase. Arch. Biochem. Biophys. (2005) 436:1-7.
  • VACCA JP: New advances in the discovery of thrombin and Factor Xa inhibitors. Curr. Opin. Chem. Biol. (2000) 25:369-383.
  • STEINMETZER T: Thrombin inhibitors. In: Enzymes and their inhibition – Drug development. Smith HJ, Simons C (Eds), CRC Press, Boca Raton, FL, USA (2005):254-268.
  • SRIVASTAVA S, GOSWAMI LN, DIKSHIT DK: Progress in the design of low molecular weight thrombin inhibitors. Med. Res. Rev. (2005) 25:66-92.
  • LEE K, JUNG WH, PARK CW, PARK HD, LEE SH, KWON OH: Noncovalent tripeptidic thrombin inhibitors incorporating amidrazone, amine and amidine functions at P1. Bioorg. Med. Chem. Lett. (2002) 12:1017-1022.
  • LEE K, PARK CW, JUNG WH et al.: Efficacious and orally bioavailable thrombin inhibitors bases on a 2,5-thienylamidine at the P1 position: discovery of N-carboxymethyl-D-diphenylalanyl-L-prolyl-[(5-amidino-2-thienyl)methyl]amide. J. Med. Chem. (2003) 46:3612-3622.
  • NUSSBAUMER P, BILLICH A: Steroid sulfatase inhibitors. Expert Opin. Ther. Patents (2003) 13:605-625.
  • HOWARTH NM, PUROHIT A, REED MJ, POTTER BV: Estrone sulfamates: potent inhibitors of estrone sulfatase with therapeutic potential. J. Med. Chem. (1994) 37:219-221.
  • WOO LW, PUROHIT A, REED MJ, POTTER BV: Active site directed inhibition of estrone sulfatase by nonsteroidal coumarin sulfamates. J. Med. Chem. (1996) 39:1349-1351.
  • POIRIER D, CIOBANU LC, MALTAIS R: Steroid sulfatase inhibitors. Expert Opin. Ther. Patents (1999) 9:1083-1099.
  • SMITH HJ, NICHOLLS PJ, SIMONS C, LE LAIN R: Inhibitors of steroidogenesis as agents for the treatment of hormone-dependent cancers. Expert Opin. Ther. Patents (2001) 11:789-824.
  • PUROHIT A, WOO LW, CHANDER SK et al.: Steroid sulphatase inhibitors for breast cancer therapy. J. Steroid Biochem. Mol. Biol. (2003) 86:423-432.
  • WOO L, LIGHTOWLER M, PUROHIT A, REED MJ, POTTER BV: Heteroatom-substituted analogues of the active site directed inhibitor. Estra-1,3,5(10)-trien-17-one-3-sulfamate inhibit estrone sulfatase by a different mechanism. J. Steroid Biochem. Molec. Biol. (1996) 57:79-88.
  • SUPURAN CT, SCOZZAFAVA A: Protein tyrosine kinase inhibitors as anticancer agents. Expert Opin. Ther. Patents (2004) 14:25-53.
  • DEWANG PM, HSU NM, PENG SZ, LI WR: Protein tyrosine phosphatases and their inhibitors. Curr. Med. Chem. (2005) 12:1-22.
  • PEI Z, LIU G, LUBBEN TH, SZCZEPANKIEWICZ BG: Inhibition of protein tyrosine phosphatase 1B as a potential treatment of diabetes and obesity. Curr. Pharm. Des. (2004) 10:3481-3504.
  • TAYLOR SD, HILL B: Recent advances in protein tyrosine phosphatase 1B inhibitors. Expert Opin. Investig. Drugs (2004) 13:199-214.
  • DADKE S, CHERNOFF J: Protein tyrosine phosphatase 1B as a potential drug target for obesity. Curr. Drug Targets Imm. Endocr. Metabol. Disord. (2003) 3:299-304.
  • BLACK E, BREED J, BREEZE AL et al.: Structure-based design of protein tyrosine phosphatase-1B inhibitors. Bioorg. Med. Chem. Lett. (2005) 15:2503-2507.

Patents

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Order Reprints Request Corporate Permissions

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

Request Academic Permissions

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.

Related research

People also read lists articles that other readers of this article have read.

Recommended articles lists articles that we recommend and is powered by our AI driven recommendation engine.

Cited by lists all citing articles based on Crossref citations.
Articles with the Crossref icon will open in a new tab.