Functionalized Organozinc Reagents in Medicinal Chemistry: Discovery of Novel Drug Candidates

Abstract

Discovery, optimization, and early development of drug candidates are very challenging and require a versatile synthetic chemistry toolbox. Organozinc chemistry is a powerful methodology for carbon–carbon bond formation which tolerates several functional groups that are critical for maintaining good physicochemical properties of drug molecules. Here we demonstrate that organozinc chemistry offers facile solutions to otherwise challenging medicinal chemistry problems commonly encountered during lead optimization. In this review, we summarize several examples in which utilization of organozinc-mediated couplings enabled us to rapidly explore a medicinal chemistry hypothesis using readily available intermediates. This chemistry allowed us to make rapid decisions with limited chemistry resources.

1 Introduction

2.1 Alpha4 Integrin Antagonists

2.2 CRTH2 Antagonists

2.3 Glucokinase (GK) Activators

2.4 Leukotriene B4 (LTB₄) Receptor Antagonists

2.5 Janus Activated Kinase 3 (JAK3) Inhibitors

2.6 Synthesis of Novel Scaffolds

3 Conclusions

4 Experimental Methods

Key words

organozinc - integrins - antagonists - activators - inhibitors

• References

• 1 Present address: TChem Consulting, LLC, Bend, OR 97701-7014, USA.
• 2a Paul SM, Mytelka DS, Dunwiddie CT, Persinger CC, Munos BH, Lindborg SR, Schacht AL. Nat. Rev. Drug Discovery 2010; 9: 203
• 2b Kesselheim AS, Avorn J. Nat. Rev. Drug Discovery 2013; 12: 425
• 3a Corey EJ, Cheng X.-M. The Logic of Chemical Synthesis . Wiley; New York: 1995
• 3b Nicolaou KC, Sorensen EJ. Classics in Total Synthesis, Part I . VCH; Weinheim: 1996
• 3c Nicolaou KC, Snyder SA. Classics in Total Synthesis, Part II . Wiley-VCH; Weinheim: 2003
• 3d Nicolaou KC, Chen JS, Edmonds DJ, Estrada AA. Angew. Chem. Int. Ed. 2009; 48: 660
• 4a Kloetzel MC. Org. React. 1948; 4: 1
• 4b Holmes HL. Org. React. 1948; 4: 60
• 4c Kagan HB, Rient O. Chem. Rev. 1992; 92: 1007
• 4d Nicolaou KC, Snyder SA, Montagnon T, Vassilikogiannakis G. Angew. Chem. Int. Ed. 2002; 41: 1668
• 5a Nielsen AT, Houlihan WJ. Org. React. 1968; 16: 1
• 5b Mukaiyam T. Org. React. 1982; 28: 203
• 6a Wittig G, Schollkopf U. Chem. Ber. 1954; 87: 1318
• 6b Wittig G, Schollkopf U. Org. Synth. Coll. Vol. V . John Wiley & Sons; London: 1973: 751
• 6c Maryanoff BE, Reitz AB. Chem. Rev. 1989; 89: 863
• 7a Grubbs RH, Brunck TK. J. Am. Chem. Soc. 1972; 94: 2538
• 7b Hong SH, Sander DP, Lee CW, Grubbs RH. J. Am. Chem. Soc. 2005; 127: 17160
• 7c Schrock RR. Acc. Chem. Res. 1990; 23: 158
• 7d Grubbs RH. Tetrahedron 1998; 54: 4413
• 7e Grubbs RH. Tetrahedron 2004; 60: 7117
• 8a Diederich F, Stang PJ. Metal-Catalyzed Cross-Coupling Reactions . Wiley-VCH; Weinheim: 1998
• 8b Miyaura N, Suzuki A. Chem. Rev. 1995; 95: 2457
• 9a Stille JK. Angew. Chem., Int. Ed. Engl. 1986; 25: 508
• 9b Farina V, Krishnamurthy V, Scott WJ. Org. React. 1998; 50: 1
• 10a Miyaura N, Suzuki A. J. Chem. Soc., Chem. Commun. 1979; 866
• 10b Suzuki A. Pure Appl. Chem. 1991; 63: 419
• 10c Suzuki A. J. Organomet. Chem. 1999; 576: 147
• 11a King AO, Okukado N, Negishi E. J. Chem. Soc., Chem. Commun. 1977; 683
• 11b Negishi E, Takahashi T, King AO. Org. Synth. Coll. Vol. VIII . John Wiley & Sons; London: 1993: 430
• 12a Rieke RD, Rhyne LD. J. Org. Chem. 1979; 44: 3445
• 12b Zhu L, Wehmeyer RM, Rieke RD. J. Org. Chem. 1991; 56: 1445
• 12c Rieke RD, Hanson MV. Tetrahedron 1997; 53: 1925
• 13a Knochel P, Yeh MC. P, Berk SC, Talbert J. J. Org. Chem. 1988; 53: 2390
• 13b Knochel P, Rozema MJ, Tucker CE, Rutherford C, Furlong M, Sidduri A. Pure Appl. Chem. 1992; 64: 361
• 13c Knochel P, Singer RD. Chem. Rev. 1993; 93: 2117
• 14a Kondo Y, Shilai M, Uchiyama M, Sakamoto T. J. Am. Chem. Soc. 1999; 121: 3539
• 14b Knochel P, Schade MA, Bernhardt S, Manolikakes G, Metzer A, Piller FM, Rohbogner CJ, Mosrin M. Beilstein J. Org. Chem. 2011; 7: 1261
• 14c Haag B, Mosrin M, Ila H, Malakhov V, Knochel P. Angew. Chem. Int. Ed. 2011; 50: 9794
• 15a Soai K, Niwa S. Chem. Rev. 1992; 92: 833
• 15b Knochel P, Vettel S, Eisenberg C. Appl. Organomet. Chem. 1995; 9: 175
• 16a de Meijere A, Diederich F, Stang PJ. Metal-Catalyzed Cross-Coupling Reactions . 2nd ed. Wiley-VCH; Weinheim: 2008
• 17a Elices MJ In Cell Adhesion Molecules Matrix Proteins . Mouse SA. Springer; Berlin: 1999: 133
• 17b Steinman L. Nat. Rev. Drug Discovery 2005; 4: 510
• 17c O’Connor P. Expert Opin. Biol. Ther. 2007; 7: 123
• 18a Tilley JW. Expert Opin. Ther. Pat. 2008; 18: 841
• 18b Davenport RJ, Munday JR. Drug Discovery Today 2007; 12: 569
• 18c Bosserhoff A.-K. Expert Opin. Ther. Pat. 2006; 16: 963
• 19a Ghosh S, Goldin E, Gordon FH, Malchow HA, Madsen JR, Rutgeerts P, Vyhnalek P, Zadorova Z, Palmer T, Donoghue S. N. Engl. J. Med. 2003; 348: 24
• 19b Holmes D. Nat. Rev. Drug Discovery 2013; 12: 411
• 20a Sidduri A, Tilley JW, Lou JP, Chen L, Kaplan G, Mennona F, Campbell R, Guthrie R, Huang T.-N, Rowan K, Schwinge V, Renzetti LM. Bioorg. Med. Chem. Lett. 2002; 12: 2479
• 20b Tilley JW, Sidduri A, Chen L, Kaplan G, Mennona F, Campbell R, Guthrie R, Huang T.-N, Rowan K, Schwinge V, Renzetti LM. Abstracts of Papers, 234th National Meeting of the American Chemical Society, Boston MA, Aug 19–23, 2007. American Chemical Society; Washington DC: 2007. MEDI125
• 21 Sircar I, Gudmundsson KS, Martin R, Liang J, Nomura S, Jayakumar H, Teegarden BR, Nowlin DM, Cardarelli PM, Mah JR, Connell S, Griffith RC, Lazarides E. Bioorg. Med. Chem. 2002; 10: 2051
• 22 Tilley JW, Sidduri A, Lou J, Kaplan J, Tare N, Cavallo G, Frank K, Pamidimukkala A, Choi AD, Gerber L, Railkar A, Renzetti LM. Bioorg. Med. Chem. Lett. 2013; 23: 1036
• 23 Sidduri A, Tilley JW, Lou J, Kaplan J, Tare N, Cavallo G, Frank K, Pamidimukkala A, Choi AD, Gerber L, Railkar A, Renzetti LM. Bioorg. Med. Chem. Lett. 2013; 23: 1026
• 24a Nagata K, Hirai H, Tanaka K, Ogawa K, Aso T, Sugamura K, Nakamura M, Takano S. FEBS Lett. 1999; 459: 195
• 24b Hirai H, Tanaka K, Yoshie O, Ogawa K, Kenmotsu K, Takamori Y, Ichimasa M, Sugamura K, Nakamura M, Takano S, Nagata K. J. Exp. Med. 2001; 193: 255
• 24c Gervais FG, Cruz RP, Chateauneuf A, Gale S, Sawyer N, Nantel F, Metters KM, O’Neill GP. J. Allergy Clin. Immunol. 2001; 108: 982
• 24d Xue L, Gyles SL, Wettey FR, Gazi L, Townsend E, Hunter MG, Pettipher R. J. Immunol. 2005; 175: 6531
• 25 Firooznia F, Gillespie P, Lin T.-A, Mertz E, Sidduri A, So S.-S, Tan J, Thakkar KC. US 8,124,629, 2012
• 26 Firooznia F, Lin T.-A, Mertz E, Sidduri A, So S.-S, Tilley JW. US 2013,150,407, 2013
• 27a Matschinsky FM. Diabetes 1996; 45: 223
• 27b Matschinsky FM. Nat. Rev. Drug Discovery 2009; 8: 399
• 28a Sarabu R, Grimsby J. Curr. Opin. Drug Discovery Dev. 2005; 8: 631
• 28b Guertin KR, Grimsby J. Curr. Med. Chem. 2006; 13: 1839
• 29 Grimsby J, Sarabu R, Corbett WL, Haynes NE, Bizzaro FT, Coffey JW, Guertin KR, Hilliard DH, Kester RF. K, Mahaney PE, Marcus L, Qi L, Spence CL, Tengi J, Magnuson MA, Chu CA, Dvorozniak MT, Matschinsky FM, Grippo JF. Science (Washington, D.C.) 2003; 301: 370
• 30 Haynes NE, Corbett WL, Bizzaro FT, Coffey JW, Guertin KR, Hilliard DH, Holland G, Kester RF. K, Mahaney PE, Marcus L, Qi L, Spence CL, Tengi J, Magnuson MA, Chu CA, Dvorozniak MT, Matschinsky FM, Grippo JF, Grimsby J, Sarabu R. J. Med. Chem. 2010; 53: 3618
• 31 Corbett WL, Sidduri A, Sarabu R. US 6,353,111, 2002
• 32 Knochel P, Janikaram Rao C. Tetrahedron 1993; 49: 29
• 33 Sidduri A, Grimsby JS, Corbett WL, Sarabu R, Grippo JF, Lou J, Kester RF, Dvorozniak M, Marcus L, Spence C, Racha JK, Moore DJ. Bioorg. Med. Chem. Lett. 2010; 20: 5673
• 34a Kim ND, Luster AD. Sci. World J. 2007; 7: 1307
• 34b Lundeen KA, Sun B, Karlsson L, Fourie AM. J. Immunol. 2006; 177: 3439
• 35a Cho K.-J, Seo J.-M, Shin Y, Yoo M.-H, Park C.-S, Lee S.-H, Chang Y.-S, Cho S.-H, Kim J.-H. Am. J. Respir. Cell Mol. Biol. 2010; 42: 294
• 35b Masclans JR, Sabater J, Sacanell J, Chacon P, Sabin P, Roca O, Planas M. Respir. Care 2007; 52: 1695
• 36 Cohen N, Lee FK.-C, Yagaloff KA. WO 9,528,386, 1995
• 37 Goodnow RA. Jr, Hicks A, Sidduri A, Kowalczyk A, Dominique R, Qiao Q, Lou J, Gillespie P, Fotouhi N, Tilley JW, Cohen N, Satish Choudhry S, Cavallo G, Tannu SA, Ventre JD, Lavelle D, Tare NS, Oh H, Lamb M, Kurylko G, Hamid R, Wright MB, Pamidimukkala A, Egan T, Gubbler U, Hoffman AF, Wei X, Li YL, O’Neil J, Marcano R, Pozzani K, Molinaro T, Santiago J, Singer L, Hargaden M, Moore DJ, Catala R, Chao LC. F, Hermann G, Venkat R, Mancebo H, Renzetti LM. J. Med. Chem. 2010; 53: 3502
• 38 Leonard WJ, O’Shea JJ. Annu. Rev. Immunol. 1998; 16: 293
• 39a Cheng AM, Rowley B, Pao W, Hayday A, Bolen JB, Pawson T. Nature (London) 1995; 378: 303
• 39b Turner M, Mee PJ, Costello PS, Williams O, Price AA, Duddy LP, Furlong MT, Geahlen RL, Tybulewicz VL. Nature (London) 1995; 378: 298
• 39c Wong BR, Grossbard EB, Payan DG, Masuda ES. Expert Opin. Invest. Drugs 2004; 13: 743
• 40 Chen S, de Vincete FJ, Hamilton MM, Hermann JC, Kennedy-Smith J, Li H, Lovely AJ, Lucas MC, Luk K.-CT, Lynch SM, O’Yang C, Padilla F, Schoenfeld RC, Sidduri A, Soth M, Wang C, Wovkulich PM, Zang X. WO 20133030138, 2013
• 41a Traxler P, Bold G, Buchdunger E, Caravatti G, Furet P, Manley P, O’Reilly T, Wood J, Zimmermann J. Med. Res. Rev. 2001; 21: 499
• 41b Doggrell SA. Expert Opin. Invest. Drugs 2005; 14: 1063
• 41c Robak T, Robak A. Expert Opin. Invest. Drugs 2012; 21: 921
• 41d Doggrell SA. Expert Opin. Invest. Drugs 2005; 14: 89
• 41e Bocchia M, Forconi F, Lauria F. Expert Opin. Emerging Drugs 2006; 11: 651
• 42 Kaplan, G.; Sidduri, A.; Tilley, J. W. unpublished large-scale procedure.
• 43 Sidduri A, Tilley JW. US 6,380,387, 2001