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The discovery of small molecule carbamates as potent dual α 4β 1/α 4β 7 integrin antagonists

Chang, Linda L ; Truong, Quang ; Mumford, Richard A ; Egger, Linda A ; Kidambi, Usha ; Lyons, Kathryn ; Mccauley, Ermengilda ; Van Riper, Gail ; Vincent, Stella ; Schmidt, John A ; Maccoss, Malcolm ; Hagmann, William K

Bioorganic & Medicinal Chemistry Letters, 2002, Vol.12(2), pp.159-163 [Peer Reviewed Journal]

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  • Title:
    The discovery of small molecule carbamates as potent dual α 4β 1/α 4β 7 integrin antagonists
  • Author: Chang, Linda L ; Truong, Quang ; Mumford, Richard A ; Egger, Linda A ; Kidambi, Usha ; Lyons, Kathryn ; Mccauley, Ermengilda ; Van Riper, Gail ; Vincent, Stella ; Schmidt, John A ; Maccoss, Malcolm ; Hagmann, William K
  • Description: The α 4β 1 and α 4β 7 integrins are implicated in several inflammatory disease states. Systematic SAR studies of an α 4β 1-specific arylsulfonyl-Pro-Tyr lead led to the identification of a new α 4β 7 binding site, best captured by O-carbamates of Tyr for this structural class. Several compounds showed a 200- to 400-fold improvement in α 4β 7 binding affinity while maintaining subnanomolar α 4β 1 activity, for example 2l, VCAM-Ig α 4β 1 IC 50=0.13 nM, VCAM-Ig α 4β 7 IC 50=1.92 nM. A series of ( N-arylsulfonyl)-Pro-Tyr-carbamates, exemplified by 2l, are potent dual α 4β 1/α 4β 7 integrin antagonists.
  • Is Part Of: Bioorganic & Medicinal Chemistry Letters, 2002, Vol.12(2), pp.159-163
  • Identifier: ISSN: 0960-894X ; E-ISSN: 1464-3405 ; DOI: 10.1016/S0960-894X(01)00710-7
  • Subjects: Medicine ; Chemistry ; Anatomy & Physiology
  • Language: English
  • Source: ScienceDirect Journals (Elsevier)

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