Abstract
Controlled microwave heating has recently emerged as an enabling and productivity-enhancing tool for the medicinal chemist. With this superheating method, reaction times can often be reduced from days and hours down to minutes, and chemistry previously considered impractical or unattainable can be accessed. In this review, the search for new protease inhibitors using microwave-assisted small-scale organic transformations is presented, with a special focus on the development of inhibitors of the aspartic proteases plasmepsin I, plasmepsin II, and HIV-1 protease. A series of rapid lead-optimizations starting from transition-state mimicking core scaffolds using mainly microwave-accelerated, palladium-catalyzed coupling reactions are presented. Biological background and test results are summarized.
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Abbreviations
- ADME:
-
Absorption, distribution, metabolism, excretion
- AIDS:
-
Acquired immunodeficiency syndrome
- Ala:
-
l-Alanine
- APC:
-
Antigen-presenting cell
- Asp:
-
l-Aspartic acid
- AZT:
-
3′Azido-2′,3′-dideoxythymidine
- Cat:
-
Cathepsin
- CoMFA:
-
Comparative molecular field analysis
- dba:
-
Dibenzylideneacetone
- DME:
-
1,2-Dimethoxyethane
- EC50 :
-
Inhibitor concentration that reduces the cytopathic effect of the virus by 50%
- ED50 :
-
Inhibitor concentration at which 50% of a given cell system is inhibited
- FDA:
-
US Food and Drug Administration
- HAART:
-
Highly active antiretroviral therapy
- HIV:
-
Human immunodeficiency virus
- K i :
-
Inhibition constant
- Leu:
-
l-Leucine
- Met:
-
l-Methionine
- MMP:
-
Matrix metalloproteinase
- MW:
-
Microwaves
- Phe:
-
l-Phenylalanine
- Plm:
-
Plasmepsin
- Pro:
-
l-Proline
- SAR:
-
Structure–activity relationship
- Tyr:
-
l-Tyrosine
References
Lidström P, Tierney J, Wathey B, Westman J (2001) Tetrahedron 57:9225
Kappe CO (2004) Angew Chem, Int Ed 43:6250
Loupy A (ed) (2002) Microwaves in organic synthesis. Wiley, Weinheim
Larhed M, Hallberg A (2001) Drug Discov Today 6:406
Kappe CO, Dallinger D (2006) Nat Rev Drug Discovery 5:51
Kappe CO, Stadler A (2005) Microwaves in organic and medicinal chemistry. Wiley, Weinheim
Roberts BA, Strauss CR (2005) Acc Chem Res 38:653
Mingos DMP, Baghurst DR (1991) Chem Soc Rev 20:1
Larhed M, Moberg C, Hallberg A (2002) Acc Chem Res 35:717
Ersmark K, Larhed M, Wannberg J (2004) Curr Opin Drug Discov Devel 7:417
Kappe CO (2002) Curr Opin Chem Biol 6:314
Baxendale IR, Lee AL, Ley SV (2005) In: Tierney JP, Lidström P (eds) Microwave assisted organic synthesis. Blackwell, Oxford, p 133
Strauss CR, Trainor RW (1995) Aust J Chem 48:1665
Ley SV, Baxendale IR (2002) Nat Rev Drug Discovery 1:573
Alterman M, Andersson HO, Garg N, Ahlsen G, Lövgren S, Classon B, Danielson UH, Kvarnström I, Vrang L, Unge T, Samuelsson B, Hallberg A (1999) J Med Chem 42:3835
Olofsson K, Larhed M (2005) In: Tierney JP, Lidström P (eds) Microwave assisted organic synthesis. Blackwell, Oxford, p 23
Tong L (2002) Chem Rev 102:4609
Schechter I, Berger A (1967) Biochem Biophys Res Commun 27:157
Cooper JB (2002) Curr Drug Targ 3:155
Leung D, Abbenante G, Fairlie DP (2000) J Med Chem 43:305
Brik A, Wong C-H (2003) Org Biomol Chem 1:5
Greenlee WJ (1987) Pharm Res 4:364
Dash C, Kulkarni A, Dunn B, Rao M (2003) Crit Rev Biochem Mol Biol 38:89
Breman JG (2001) Am J Trop Med Hyg 64:1
Gardner MJ, Hall N, Fung E, White O, Berriman M, Hyman RW, Carlton JM, Pain A, Nelson KE, Bowman S, Paulsen IT, James K, Eisen JA, Rutherford K, Salzberg SL, Craig A, Kyes S, Chan M-S, Nene V, Shallom SJ, Suh B, Peterson J, Angiuoli S, Pertea M, Allen J, Selengut J, Haft D, Mather MW, Vaidya AB, Martin DMA, Fairlamb AH, Fraunholz MJ, Roos DS, Ralph SA, McFadden GI, Cummings LM, Subramanian GM, Mungall C, Venter JC, Carucci DJ, Hoffman SL, Newbold C, Davis RW, Fraser CM, Barrell B (2002) Nature 419:498
Berry C (2000) Curr Opin Drug Discov Dev 3:624
Boss C, Richard-Bildstein S, Weller T, Fischli W, Meyer S, Binkert C (2003) Curr Med Chem 10:883
Ersmark K, Samuelsson B, Hallberg A (2006) Med Res Rev 26(5):626
Silva AM, Lee AY, Gulnik SV, Maier P, Collins J, Bhat TN, Collins PJ, Cachau RE, Luker KE, Gluzman IY, Francis SE, Oksman A, Goldberg DE, Erickson JW (1996) Proc Natl Acad Sci USA 93:10034
Haque TS, Skillman AG, Lee CE, Habashita H, Gluzman IY, Ewing TJ, Goldberg DE, Kuntz ID, Ellman JA (1999) J Med Chem 42:1428
Nöteberg D, Hamelink E, Hulten J, Wahlgren M, Vrang L, Samuelsson B, Hallberg A (2003) J Med Chem 46:734
Nöteberg D, Schaal W, Hamelink E, Vrang L, Larhed M (2003) J Comb Chem 5:456
Muthas D, Nöteberg D, Sabnis YA, Hamelink E, Vrang L, Samuelsson B, Karlen A, Hallberg A (2005) Bioorg Med Chem 13:5371
Ersmark K, Feierberg I, Bjelic S, Hultén J, Samuelsson B, Aqvist J, Hallberg A (2003) Bioorg Med Chem 11:3723
Ersmark K, Feierberg I, Bjelic S, Hamelink E, Hackett F, Blackman MJ, Hulten J, Samuelsson B, Aqvist J, Hallberg A (2004) J Med Chem 47:110
Ersmark K, Nervall M, Hamelink E, Janka LK, Clemente JC, Dunn BM, Blackman MJ, Samuelsson B, Aqvist J, Hallberg A (2005) J Med Chem 48:6090
Netherton MR, Fu GC (2001) Org Lett 3:4295
CDC (1981) MMWR Morb Mortal Wkly Rep 30:250
CDC (1981) MMWR Morb Mortal Wkly Rep 30:305
Gottlieb MS, Schroff R, Schanker HM, Weisman JD, Fan PT, Wolf RA, Saxon A (1981) N Engl J Med 305:1425
Masur H, Michelis MA, Greene JB, Onorato I, Stouwe RA, Holzman RS, Wormser G, Brettman L, Lange M, Murray HW, Cunningham-Rundles S (1981) N Engl J Med 305:1431
Gottlieb MS, Schroff R, Schanker HM, Weisman JD, Fan PT, Wolf RA, Saxon A, Mannucci PM, Vigano S (1982) MMWR Morb Mortal Wkly Rep 31:507
CDC (1982) N Engl J Med 306:248
Dalgleish AG, Beverley PC, Clapham PR, Crawford DH, Greaves MF, Weiss RA (1984) Nature 312:763
Klatzmann D, Champagne E, Chamaret S, Gruest J, Guetard D, Hercend T, Gluckman JC, Montagnier L (1984) Nature 312:767
Fischl MA, Richman DD, Grieco MH, Gottlieb MS, Volberding PA, Laskin OL, Leedom JM, Groopman JE, Mildvan D, Schooley RT, Jackson GG, Durack DT, King D (1987) N Engl J Med 317:185
Richman DD, Fischl MA, Grieco MH, Gottlieb MS, Volberding PA, Laskin OL, Leedom JM, Groopman JE, Mildvan D, Hirsch MS, Jackson GG, Durack DT, Nusinofflehrman S (1987) N Engl J Med 317:192
De Clercq E (2005) J Med Chem 48:1297
Huff JR (1991) J Med Chem 34:2305
Swanstrom R, Erona J (2000) Pharmacol Ther 86:145
Tomasselli AG, Heinrikson RL (2000) Biochim Biophys Acta 1477:189
Huff JR, Kahn J (2001) Adv Protein Chem 56:213
Erickson JW, Gulnik SV, Markowitz M (1999) Aids 13 Suppl A:S189
Palella FJ Jr, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, Aschman DJ, Holmberg SD (1998) N Engl J Med 338:853
Mocroft A, Vella S, Benfield TL, Chiesi A, Miller V, Gargalianos P, d'Arminio Monforte A, Yust I, Bruun JN, Phillips AN, Lundgren JD (1998) Lancet 352:1725
Fellay J, Boubaker K, Ledergerber B, Bernasconi E, Furrer H, Battegay M, Hirschel B, Vernazza P, Francioli P, Greub G, Flepp M, Telenti A (2001) Lancet 358:1322
Clavel F, Hance AJ (2004) N Engl J Med 350:1023
Alterman M, Björsne M, Muehlman A, Classon B, Kvarnström I, Danielson H, Markgren P-O, Nillroth U, Unge T, Hallberg A, Samuelsson B (1998) J Med Chem 41:3782
Larhed M, Lindeberg G, Hallberg A (1996) Tetrahedron Lett 37:8219
Larhed M, Hallberg A (1996) J Org Chem 61:9582
Alterman M, Hallberg A (2000) J Org Chem 65:7984
Beller M, Cornils B, Frohning CD, Kohlpaintner CW (1995) J Mol Cat A: Chemical 104:17
Skoda-Foldes R, Kollar L (2002) Curr Org Chem 6:1097
Wannberg J, Larhed M (2003) J Org Chem 68:5750
Wannberg J, Dallinger D, Kappe CO, Larhed M (2005) J Comb Chem 7:574
Wannberg J, Kaiser N-FK, Vrang L, Samuelsson B, Larhed M, Hallberg A (2005) J Comb Chem 7:611
Negishi E-i (2002) Handbook of organopalladium chemistry for organic synthesis, vol 1. Wiley, New York
Wannberg J, Sabnis YA, Vrang L, Samuelsson B, Karlen A, Hallberg A, Larhed M (2006) Bioorg Med Chem 14:5303
Wu X, Wannberg J, Larhed M (2006) Tetrahedron 62:4665
Ekegren JK, Unge T, Safa MZ, Wallberg H, Samuelsson B, Hallberg A (2005) J Med Chem 48:8098
Ekegren JK, Ginman N, Johansson A, Wallberg H, Larhed M, Samuelsson B, Unge T, Hallberg A (2006) J Med Chem 49:1828
Wu X, Ekegren JK, Larhed M (2006) Organometallics 25:1434
Hulten J, Bonham NM, Nillroth U, Hansson T, Zuccarello G, Bouzide A, Aqvist J, Classon B, Danielson UH, Karlen A, Kvarnström I, Samuelsson B, Hallberg A (1997) J Med Chem 40:885
Hulten J, Andersson HO, Schaal W, Danielson HU, Classon B, Kvarnström I, Karlen A, Unge T, Samuelsson B, Hallberg A (1999) J Med Chem 42:4054
Backbro K, Löwgren S, Österlund K, Atepo J, Unge T, Hulten J, Bonham NM, Schaal W, Karlen A, Hallberg A (1997) J Med Chem 40:898
Lam PYS, Jadhav PK, Eyermann CJ, Hodge CN, Ru Y, Bacheler LT, Meek OMJ, Rayner MM (1994) Science 263:380
Cramer RD, Patterson DE, Bunce JD (1988) J Am Chem Soc 110:5959
Schaal W, Karlsson A, Ahlsen G, Lindberg J, Andersson HO, Danielson UH, Classon B, Unge T, Samuelsson B, Hulten J, Hallberg A, Karlen A (2001) J Med Chem 44:155
Ax A, Schaal W, Vrang L, Samuelsson B, Hallberg A, Karlen A (2005) Bioorg Med Chem 13:755
Gold H, Ax A, Vrang L, Samuelsson B, Karlen A, Hallberg A, Larhed M (2006) Tetrahedron 62:4671
Gold H, Larhed M, Nilsson P (2005) Synlett, p 1596
Shepard Colin W, Finelli L, Alter Miriam J (2005) Lancet Infect Dis 5:558
Wu X, Rönn R, Gossas T, Larhed M (2005) J Org Chem 70:3094
Hopkins C, Neuenschwander K, Scotese A, Jackson S, Nieduzak T, Pauls H, Liang G, Sides K, Cramer D, Cairns J, Maignan S, Mathieu M (2004) Bioorg Med Chem Lett 14:4819
Roehrig S, Straub A, Pohlmann J, Lampe T, Pernerstorfer J, Schlemmer K-H, Reinemer P, Perzborn E (2005) J Med Chem 48:5900
Nantermet PG, Barrow JC, Newton CL, Pellicore JM, Young M, Lewis SD, Lucas BJ, Krueger JA, McMasters DR, Yan Y, Kuo LC, Vacca JP, Selnick HG (2003) Bioorg Med Chem Lett 13:2781
Loeser R, Schilling K, Dimmig E, Guetschow M (2005) J Med Chem 48:7688
Kravchenko DV, Kysil VV, Ilyn AP, Tkachenko SE, Maliarchouk S, Okun IM, Ivachtchenko AV (2005) Bioorg Med Chem Lett 15:1841
Hu Y, Xiang JS, DiGrandi MJ, Du X, Ipek M, Laakso LM, Li J, Li W, Rush TS, Schmid J, Skotnicki JS, Tam S, Thomason JR, Wang Q, Levin JI (2005) Bioorg Med Chem 13:6629
Acknowledgments
We gratefully acknowledge the Swedish Research Council (VR), the Swedish Foundation for Strategic Research (SSF), Medivir AB, Dr Jenny Ekegren, Dr Kristofer Olofsson and Mr Gunnar Wikman for valuable help and support.
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Wannberg, J., Ersmark, K., Larhed, M. (2006). Microwave-Accelerated Synthesis of Protease Inhibitors. In: Larhed, M., Olofssonq, K. (eds) Microwave Methods in Organic Synthesis. Topics in Current Chemistry, vol 266. Springer, Berlin, Heidelberg . https://doi.org/10.1007/128_067
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