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Microwave-Accelerated Synthesis of Protease Inhibitors

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Microwave Methods in Organic Synthesis

Part of the book series: Topics in Current Chemistry ((TOPCURRCHEM,volume 266))

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

  1. Lidström P, Tierney J, Wathey B, Westman J (2001) Tetrahedron 57:9225

    Article  Google Scholar 

  2. Kappe CO (2004) Angew Chem, Int Ed 43:6250

    Article  CAS  Google Scholar 

  3. Loupy A (ed) (2002) Microwaves in organic synthesis. Wiley, Weinheim

    Book  Google Scholar 

  4. Larhed M, Hallberg A (2001) Drug Discov Today 6:406

    Article  CAS  Google Scholar 

  5. Kappe CO, Dallinger D (2006) Nat Rev Drug Discovery 5:51

    Article  CAS  Google Scholar 

  6. Kappe CO, Stadler A (2005) Microwaves in organic and medicinal chemistry. Wiley, Weinheim

    Book  Google Scholar 

  7. Roberts BA, Strauss CR (2005) Acc Chem Res 38:653

    Article  CAS  Google Scholar 

  8. Mingos DMP, Baghurst DR (1991) Chem Soc Rev 20:1

    Article  CAS  Google Scholar 

  9. Larhed M, Moberg C, Hallberg A (2002) Acc Chem Res 35:717

    Article  CAS  Google Scholar 

  10. Ersmark K, Larhed M, Wannberg J (2004) Curr Opin Drug Discov Devel 7:417

    CAS  Google Scholar 

  11. Kappe CO (2002) Curr Opin Chem Biol 6:314

    Article  CAS  Google Scholar 

  12. Baxendale IR, Lee AL, Ley SV (2005) In: Tierney JP, Lidström P (eds) Microwave assisted organic synthesis. Blackwell, Oxford, p 133

    Chapter  Google Scholar 

  13. Strauss CR, Trainor RW (1995) Aust J Chem 48:1665

    Article  CAS  Google Scholar 

  14. Ley SV, Baxendale IR (2002) Nat Rev Drug Discovery 1:573

    Article  CAS  Google Scholar 

  15. 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

    Article  CAS  Google Scholar 

  16. Olofsson K, Larhed M (2005) In: Tierney JP, Lidström P (eds) Microwave assisted organic synthesis. Blackwell, Oxford, p 23

    Chapter  Google Scholar 

  17. Tong L (2002) Chem Rev 102:4609

    Article  CAS  Google Scholar 

  18. Schechter I, Berger A (1967) Biochem Biophys Res Commun 27:157

    Article  CAS  Google Scholar 

  19. Cooper JB (2002) Curr Drug Targ 3:155

    Article  CAS  Google Scholar 

  20. Leung D, Abbenante G, Fairlie DP (2000) J Med Chem 43:305

    Article  CAS  Google Scholar 

  21. Brik A, Wong C-H (2003) Org Biomol Chem 1:5

    Article  CAS  Google Scholar 

  22. Greenlee WJ (1987) Pharm Res 4:364

    Article  CAS  Google Scholar 

  23. Dash C, Kulkarni A, Dunn B, Rao M (2003) Crit Rev Biochem Mol Biol 38:89

    Article  CAS  Google Scholar 

  24. Breman JG (2001) Am J Trop Med Hyg 64:1

    CAS  Google Scholar 

  25. 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

    Article  CAS  Google Scholar 

  26. Berry C (2000) Curr Opin Drug Discov Dev 3:624

    CAS  Google Scholar 

  27. Boss C, Richard-Bildstein S, Weller T, Fischli W, Meyer S, Binkert C (2003) Curr Med Chem 10:883

    Article  CAS  Google Scholar 

  28. Ersmark K, Samuelsson B, Hallberg A (2006) Med Res Rev 26(5):626

    Article  CAS  Google Scholar 

  29. 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

    Article  CAS  Google Scholar 

  30. Haque TS, Skillman AG, Lee CE, Habashita H, Gluzman IY, Ewing TJ, Goldberg DE, Kuntz ID, Ellman JA (1999) J Med Chem 42:1428

    Article  CAS  Google Scholar 

  31. Nöteberg D, Hamelink E, Hulten J, Wahlgren M, Vrang L, Samuelsson B, Hallberg A (2003) J Med Chem 46:734

    Article  CAS  Google Scholar 

  32. Nöteberg D, Schaal W, Hamelink E, Vrang L, Larhed M (2003) J Comb Chem 5:456

    Article  CAS  Google Scholar 

  33. Muthas D, Nöteberg D, Sabnis YA, Hamelink E, Vrang L, Samuelsson B, Karlen A, Hallberg A (2005) Bioorg Med Chem 13:5371

    Article  CAS  Google Scholar 

  34. Ersmark K, Feierberg I, Bjelic S, Hultén J, Samuelsson B, Aqvist J, Hallberg A (2003) Bioorg Med Chem 11:3723

    Article  CAS  Google Scholar 

  35. 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

    Article  CAS  Google Scholar 

  36. 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

    Article  CAS  Google Scholar 

  37. Netherton MR, Fu GC (2001) Org Lett 3:4295

    Article  CAS  Google Scholar 

  38. CDC (1981) MMWR Morb Mortal Wkly Rep 30:250

    Google Scholar 

  39. CDC (1981) MMWR Morb Mortal Wkly Rep 30:305

    Google Scholar 

  40. Gottlieb MS, Schroff R, Schanker HM, Weisman JD, Fan PT, Wolf RA, Saxon A (1981) N Engl J Med 305:1425

    Article  CAS  Google Scholar 

  41. 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

    Article  CAS  Google Scholar 

  42. 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

    Google Scholar 

  43. CDC (1982) N Engl J Med 306:248

    Google Scholar 

  44. Dalgleish AG, Beverley PC, Clapham PR, Crawford DH, Greaves MF, Weiss RA (1984) Nature 312:763

    Article  CAS  Google Scholar 

  45. Klatzmann D, Champagne E, Chamaret S, Gruest J, Guetard D, Hercend T, Gluckman JC, Montagnier L (1984) Nature 312:767

    Article  CAS  Google Scholar 

  46. 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

    Article  CAS  Google Scholar 

  47. 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

    Article  CAS  Google Scholar 

  48. De Clercq E (2005) J Med Chem 48:1297

    Article  CAS  Google Scholar 

  49. Huff JR (1991) J Med Chem 34:2305

    Article  CAS  Google Scholar 

  50. Swanstrom R, Erona J (2000) Pharmacol Ther 86:145

    Article  CAS  Google Scholar 

  51. Tomasselli AG, Heinrikson RL (2000) Biochim Biophys Acta 1477:189

    Article  CAS  Google Scholar 

  52. Huff JR, Kahn J (2001) Adv Protein Chem 56:213

    Article  CAS  Google Scholar 

  53. Erickson JW, Gulnik SV, Markowitz M (1999) Aids 13 Suppl A:S189

    Google Scholar 

  54. Palella FJ Jr, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, Aschman DJ, Holmberg SD (1998) N Engl J Med 338:853

    Article  Google Scholar 

  55. 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

    Article  CAS  Google Scholar 

  56. 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

    Article  CAS  Google Scholar 

  57. Clavel F, Hance AJ (2004) N Engl J Med 350:1023

    Article  CAS  Google Scholar 

  58. 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

    Article  CAS  Google Scholar 

  59. Larhed M, Lindeberg G, Hallberg A (1996) Tetrahedron Lett 37:8219

    Article  CAS  Google Scholar 

  60. Larhed M, Hallberg A (1996) J Org Chem 61:9582

    Article  CAS  Google Scholar 

  61. Alterman M, Hallberg A (2000) J Org Chem 65:7984

    Article  CAS  Google Scholar 

  62. Beller M, Cornils B, Frohning CD, Kohlpaintner CW (1995) J Mol Cat A: Chemical 104:17

    Article  CAS  Google Scholar 

  63. Skoda-Foldes R, Kollar L (2002) Curr Org Chem 6:1097

    Article  CAS  Google Scholar 

  64. Wannberg J, Larhed M (2003) J Org Chem 68:5750

    Article  CAS  Google Scholar 

  65. Wannberg J, Dallinger D, Kappe CO, Larhed M (2005) J Comb Chem 7:574

    Article  CAS  Google Scholar 

  66. Wannberg J, Kaiser N-FK, Vrang L, Samuelsson B, Larhed M, Hallberg A (2005) J Comb Chem 7:611

    Article  CAS  Google Scholar 

  67. Negishi E-i (2002) Handbook of organopalladium chemistry for organic synthesis, vol 1. Wiley, New York

    Google Scholar 

  68. Wannberg J, Sabnis YA, Vrang L, Samuelsson B, Karlen A, Hallberg A, Larhed M (2006) Bioorg Med Chem 14:5303

    Article  CAS  Google Scholar 

  69. Wu X, Wannberg J, Larhed M (2006) Tetrahedron 62:4665

    Article  CAS  Google Scholar 

  70. Ekegren JK, Unge T, Safa MZ, Wallberg H, Samuelsson B, Hallberg A (2005) J Med Chem 48:8098

    Article  CAS  Google Scholar 

  71. Ekegren JK, Ginman N, Johansson A, Wallberg H, Larhed M, Samuelsson B, Unge T, Hallberg A (2006) J Med Chem 49:1828

    Article  CAS  Google Scholar 

  72. Wu X, Ekegren JK, Larhed M (2006) Organometallics 25:1434

    Article  CAS  Google Scholar 

  73. 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

    Article  CAS  Google Scholar 

  74. 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

    Article  CAS  Google Scholar 

  75. 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

    Article  CAS  Google Scholar 

  76. Lam PYS, Jadhav PK, Eyermann CJ, Hodge CN, Ru Y, Bacheler LT, Meek OMJ, Rayner MM (1994) Science 263:380

    Article  CAS  Google Scholar 

  77. Cramer RD, Patterson DE, Bunce JD (1988) J Am Chem Soc 110:5959

    Article  CAS  Google Scholar 

  78. 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

    Article  CAS  Google Scholar 

  79. Ax A, Schaal W, Vrang L, Samuelsson B, Hallberg A, Karlen A (2005) Bioorg Med Chem 13:755

    Article  CAS  Google Scholar 

  80. Gold H, Ax A, Vrang L, Samuelsson B, Karlen A, Hallberg A, Larhed M (2006) Tetrahedron 62:4671

    Article  CAS  Google Scholar 

  81. Gold H, Larhed M, Nilsson P (2005) Synlett, p 1596

    Google Scholar 

  82. Shepard Colin W, Finelli L, Alter Miriam J (2005) Lancet Infect Dis 5:558

    Article  CAS  Google Scholar 

  83. Wu X, Rönn R, Gossas T, Larhed M (2005) J Org Chem 70:3094

    Article  CAS  Google Scholar 

  84. 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

    Article  CAS  Google Scholar 

  85. Roehrig S, Straub A, Pohlmann J, Lampe T, Pernerstorfer J, Schlemmer K-H, Reinemer P, Perzborn E (2005) J Med Chem 48:5900

    Article  CAS  Google Scholar 

  86. 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

    Article  CAS  Google Scholar 

  87. Loeser R, Schilling K, Dimmig E, Guetschow M (2005) J Med Chem 48:7688

    Article  CAS  Google Scholar 

  88. Kravchenko DV, Kysil VV, Ilyn AP, Tkachenko SE, Maliarchouk S, Okun IM, Ivachtchenko AV (2005) Bioorg Med Chem Lett 15:1841

    Article  CAS  Google Scholar 

  89. 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

    Article  CAS  Google Scholar 

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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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Authors and Affiliations

  1. Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, BMC, Uppsala University, Box 574, 75123, Uppsala, Sweden

    Johan Wannberg

  2. Department of Chemistry, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montréal, Québec, Canada

    Karolina Ersmark

  3. Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, BMC, Uppsala University, Box 574, 75123, Uppsala, Sweden

    Mats Larhed

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  1. Johan Wannberg
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  2. Karolina Ersmark
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  3. Mats Larhed
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Correspondence to Mats Larhed .

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Mats Larhed Kristofer Olofssonq

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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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