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N-Isonicotinoyl-(l)-4-aminophenylalanine derivatives as tight binding VLA-4 antagonists

Doherty, George A. ; Yang, Ginger X. ; Borges, Edite ; Tong, Sharon ; Mccauley, Ermengilda D. ; Treonz, Kelly M. ; Van Riper, Gail ; Pacholok, Stephen ; Si, Qian ; Koo, Gloria C. ; Shah, Kashmira ; Mumford, Richard A. ; Hagmann, William K.

Bioorganic & Medicinal Chemistry Letters, 6/2003, Vol.13(11), pp.1891-1895 [Peer Reviewed Journal]

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  • Title:
    N-Isonicotinoyl-(l)-4-aminophenylalanine derivatives as tight binding VLA-4 antagonists
  • Author: Doherty, George A. ; Yang, Ginger X. ; Borges, Edite ; Tong, Sharon ; Mccauley, Ermengilda D. ; Treonz, Kelly M. ; Van Riper, Gail ; Pacholok, Stephen ; Si, Qian ; Koo, Gloria C. ; Shah, Kashmira ; Mumford, Richard A. ; Hagmann, William K.
  • Description: A series of isonicotinoyl-( l)-aminophenylalanine derivatives was prepared and evaluated as VLA-4 antagonists. These compounds exhibit subnanomolar binding affinity to VLA-4 and significant off-rates. The interplay between off-rate, protein binding and pharmacokinetics is discussed. A series of isonicotinoyl-( l)-aminophenylalanine derivatives was prepared and evaluated as VLA-4 antagonists. These compounds exhibit subnanomolar binding affinity to activated and unactivated states of VLA-4 and significant off-rates. The best compound reported 5 shows activity in reducing eosinophil trafficking in an OVA asthma model even though it is highly protein bound and rapidly cleared from the plasma. The interplay between off-rate, protein binding and pharmacokinetics is discussed.
  • Is Part Of: Bioorganic & Medicinal Chemistry Letters, 6/2003, Vol.13(11), pp.1891-1895
  • Identifier: ISSN: 0960894X ; DOI: http://dx.doi.org/10.1016/S0960-894X(03)00308-1
  • Subjects: Medicine ; Chemistry ; Anatomy & Physiology
  • Language: English

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