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Synthesis 2002(14): 2023-2036
DOI: 10.1055/s-2002-34389
PAPER
© Georg Thieme Verlag Stuttgart · New York

Aromatic β-Amino Acids as Asp-Phg Mimics in LDV Derived VLA-4 Antagonists­

Volkmar Wehner*a, Horst Blumb, Michael Kurza, Hans Ulrich Stilza
a Chemistry, Aventis Pharma Deutschland GmbH, 65926 Frankfurt am Main, Germany
Fax: +490(69)331399; e-Mail: volkmar.wehner@aventis.com;
b DG Thrombotic/Degenerative Joint Diseases, Aventis Pharma Deutschland GmbH, 65926 Frankfurt am Main, Germany
Further Information

Publication History

Received 28 June 2002
Publication Date:
26 September 2002 (online)

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Abstract

Aromatic β-amino acid esters 2a-h were prepared in racemic and enantiomerically pure form by the Radionow reaction or based on the method described by Davis and used as mimics of the Asp-Phg C-terminus in LDV derived VLA-4 antagonists. As a promising β-amino acid ester, 11 was identified and used for the synthesis of the highly potent VLA-4 antagonist S9059 with an IC50 of 1.6 nM in a cell attachment assay.

Key words

amino acids - esters - asymmetric synthesis - chiral auxiliaries - VLA-4 antagonists

    References

  • 1a Hintermann T. Seebach D. Chimia  1997,  50:  244 
    CrossrefPubMedGoogle Scholar
  • 1b Seebach D. Albert M. Arvidsson PI. Rueping M. Schreiber JV. Chimia  2001,  55:  345 
    CrossrefPubMedGoogle Scholar
  • 1c Frackenpohl J. Arvidsson PI. Schreiber JV. Seebach D. ChemBioChem  2001,  2:  445 
    CrossrefPubMedGoogle Scholar
  • 2 Gademann K. Ernst M. Hoyer D. Seebach D. Angew. Chem.ŽInt. Ed.  1999,  111: 1223; Angew. Chem. 1999, 111, 1302
    Google Scholar
  • 3 Gademann K. Kimmerlin T. Hoyer D. Seebach D. J. Med. Chem.  2001,  44:  2460 
    CrossrefGoogle Scholar
  • 4 Gademann K. Seebach D. Helv. Chim. Acta  2001,  84:  2924 
    CrossrefGoogle Scholar
  • 5 Stilz HU. Guba W. Jablonka B. Just M. Klingler O. König W. Wehner V. Zoller G. J. Med. Chem.  2001,  44:  1158  ; and literature cited therein
    CrossrefGoogle Scholar
  • 6 Tilley JW. Sidduri A. Drugs Future  2001,  26:  985 
    Google Scholar
  • 7a Holland GW. Kassir JM. Scott IL. TBC3486: Novel highly potent and selective VLA-4 antagonist   219th ACS Natl Meeting, ACS; Washington DC: 2000. 
    Google Scholar
  • 7b Kassir JM. Scott IL. Biediger RJ. Novel NN disubstituted amides that are highly potent VLA-4 antagonist   219th ACS Natl Meeting, ACS; Washington DC: 2000. 
    Google Scholar
  • 7c Scott IL. Raju BG. Ren K. Novel urea derivatives that are highly potent VLA-4 antagonist   219th ACS Natl Meeting, ACS; Washington DC: 2000. 
    Google Scholar
  • 8a Radionow WM. Postovskaja EA. J. Am. Chem. Soc.  1929,  51:  847 
    CrossrefGoogle Scholar
  • 8b Radionow WM. J. Am. Chem. Soc.  1929,  51:  847 
    CrossrefGoogle Scholar
  • 9a Secor HV. Edwards WB. J. Org. Chem.  1979,  44:  3136 
    CrossrefGoogle Scholar
  • 9b Furukawa M. Okawara T. Noguchi Y. Terawaki Y. Chem. Pharm. Bull.  1978,  26:  260 
    CrossrefGoogle Scholar
  • 9c Bovy RP. Rico JG. Tetrahedron Lett.  1993,  34:  8015 
    CrossrefGoogle Scholar
  • 9d Robinson AJ. Wyatt PB. Tetrahedron  1993,  49:  11329 
    CrossrefGoogle Scholar
  • 10 Soloshonok VA. Fokina NA. Rybakova AV. Shishkina IP. Golushko SV. Sorochinsky AE. Kukhar VP. Tetrahedron: Asymmetry  1995,  6:  1601 
    CrossrefGoogle Scholar
  • 11a Davis SG. Ichihara O. Tetrahedron: Asymmetry  1991,  2:  183 
    CrossrefGoogle Scholar
  • 11b Davis SG. Garrido NM. Ichihara O. Walters IA. J. Chem. Soc., Chem. Commun.  1993,  1153 
    CrossrefGoogle Scholar
  • 12a Guichard G. Abele S. Seebach D. Helv. Chim. Acta  1998,  81:  187 
    Google Scholar
  • 12b Podlech J. Seebach D. Liebigs Ann. Chem.  1995,  1217 
    Google Scholar
  • 12c Matthews JL. Braun C. Guibourdenche C. Overhand M. Seebach D. In Enantioselective Synthesis of β-Amino Acids   Wiley-VCH; New York: 1997.  p.105 
    Google Scholar
  • 13 Juaristi EM. Seebach D. In Enantioselective Synthesis of β-Amino Acids   Wiley-VCH; New York: 1997.  p.261 
    Google Scholar
  • 14 Abele S. Seebach D. Eur. J. Org. Chem.  2000,  1 
    Google Scholar
  • 15 Nowick JS. Holmes DL. Noronha G. Smith EM. Nguyen TM. Huang S.-L. J. Org. Chem.  1996,  61:  3929 
    CrossrefPubMedGoogle Scholar