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

Volkmar  Wehner; Horst  Blum; Michael  Kurz; Hans Ulrich  Stilz

doi:10.1055/s-2002-34389

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

Volkmar Wehner*^a, Horst Blum^b, Michael Kurz^a, Hans Ulrich Stilz^a
^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

Abstract

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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

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Referenzen

References

1a Hintermann T. Seebach D. Chimia 1997, 50: 244

1b Seebach D. Albert M. Arvidsson PI. Rueping M. Schreiber JV. Chimia 2001, 55: 345

1c Frackenpohl J. Arvidsson PI. Schreiber JV. Seebach D. ChemBioChem 2001, 2: 445

2 Gademann K. Ernst M. Hoyer D. Seebach D. Angew. Chem.ŽInt. Ed. 1999, 111: 1223; Angew. Chem. 1999, 111, 1302

3 Gademann K. Kimmerlin T. Hoyer D. Seebach D. J. Med. Chem. 2001, 44: 2460

4 Gademann K. Seebach D. Helv. Chim. Acta 2001, 84: 2924

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

6 Tilley JW. Sidduri A. Drugs Future 2001, 26: 985

7a Holland GW. Kassir JM. Scott IL. TBC3486: Novel highly potent and selective VLA-4 antagonist 219th ACS Natl Meeting, ACS; Washington DC: 2000.

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.

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.

8a Radionow WM. Postovskaja EA. J. Am. Chem. Soc. 1929, 51: 847

8b Radionow WM. J. Am. Chem. Soc. 1929, 51: 847

9a Secor HV. Edwards WB. J. Org. Chem. 1979, 44: 3136

9b Furukawa M. Okawara T. Noguchi Y. Terawaki Y. Chem. Pharm. Bull. 1978, 26: 260

9c Bovy RP. Rico JG. Tetrahedron Lett. 1993, 34: 8015

9d Robinson AJ. Wyatt PB. Tetrahedron 1993, 49: 11329

10 Soloshonok VA. Fokina NA. Rybakova AV. Shishkina IP. Golushko SV. Sorochinsky AE. Kukhar VP. Tetrahedron: Asymmetry 1995, 6: 1601

11a Davis SG. Ichihara O. Tetrahedron: Asymmetry 1991, 2: 183

11b Davis SG. Garrido NM. Ichihara O. Walters IA. J. Chem. Soc., Chem. Commun. 1993, 1153

12a Guichard G. Abele S. Seebach D. Helv. Chim. Acta 1998, 81: 187

12b Podlech J. Seebach D. Liebigs Ann. Chem. 1995, 1217

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

13 Juaristi EM. Seebach D. In Enantioselective Synthesis of β-Amino Acids Wiley-VCH; New York: 1997. p.261

14 Abele S. Seebach D. Eur. J. Org. Chem. 2000, 1

15 Nowick JS. Holmes DL. Noronha G. Smith EM. Nguyen TM. Huang S.-L. J. Org. Chem. 1996, 61: 3929

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

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