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N-(3-Phenylsulfonyl-3-piperidinoyl)-phenylalanine derivatives as potent, selective VLA-4 antagonists

Gutteridge, Clare E ; de Laszlo, Stephen E ; Kamenecka, Theodore M ; Mccauley, Ermengilda ; van Riper, Gail ; Mumford, Richard A ; Kidambi, Usha ; Egger, Linda A ; Tong, Sharon ; Hagmann, William K

Bioorganic & Medicinal Chemistry Letters, 2003, Vol.13(5), pp.885-890 [Peer Reviewed Journal]

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  • Title:
    N-(3-Phenylsulfonyl-3-piperidinoyl)-phenylalanine derivatives as potent, selective VLA-4 antagonists
  • Author: Gutteridge, Clare E ; de Laszlo, Stephen E ; Kamenecka, Theodore M ; Mccauley, Ermengilda ; van Riper, Gail ; Mumford, Richard A ; Kidambi, Usha ; Egger, Linda A ; Tong, Sharon ; Hagmann, William K
  • Description: The SAR of 1-sulfonyl-cyclopentyl carboxylic acid amides, ligands for the VLA-4 integrin, was investigated. This effort resulted in the identification of N-(3-phenylsulfonyl-3-piperidinoyl)-( l)-4-(2′,6′-dimethoxyphenyl)phenylalanine 52 as a potent, selective VLA-4 antagonist (IC 50=90 pM). Expansion of the SAR demonstrated that this structural unit can be used to identify a diverse series of sub-nanomolar antagonists. Optimization of a lead from a chemical library afforded the novel VLA-4 antagonist N-(α- p-fluorophenylsulfonyl-cyclopentanoyl)-2′,6′-dimethoxyphenylalanine (VLA-4 IC 50=0.07 nM). Subsequent optimization for selectivity versus the related integrin α 4β 7 led to discovery of N-(3-phenylsulfonyl-3-piperidinoyl)-phenylalanine 52 (VLA-4 IC 50=0.09 nM, α 4β 7 IC 50=168 nM).
  • Is Part Of: Bioorganic & Medicinal Chemistry Letters, 2003, Vol.13(5), pp.885-890
  • Identifier: ISSN: 0960-894X ; E-ISSN: 1464-3405 ; DOI: 10.1016/S0960-894X(02)01077-6
  • Subjects: Medicine ; Chemistry ; Anatomy & Physiology
  • Language: English

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