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

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 
• 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