181517-99-7Relevant articles and documents
Selective, tight-binding inhibitors of integrin α4β1 that inhibit allergic airway responses
Lin, Ko-Chung,Ateeq, Humayun S.,Hsiung, Sherry H.,Chong, Lillian T.,Zimmerman, Craig N.,Castro, Alfredo,Lee, Wen-Cherng,Hammond, Charles E.,Kalkunte, Sandhya,Chen, Ling-Ling,Pepinsky, R. Blake,Leone, Diane R.,Sprague, Andrew G.,Abraham, William M.,Gill, Alan,Lobb, Roy R.,Adams, Steven P.
, p. 920 - 934 (1999)
Integrin α4β1 mediates leukocyte recruitment, activation, mediator release, and apoptosis inhibition, and it plays a central role in inflammatory pathophysiology. High-affinity, selective inhibitors of α4β1, based on the Leu-Asp-Val (LDV) sequence from the alternatively spliced connecting segment-1 (CS-1) peptide of cellular fibronectin, are described that employ a novel N-terminal peptide 'cap' strategy. One inhibitor, BIO- 1211, was ~106-fold more potent than the starting peptide and exhibited tight-binding properties (k(off) = 1.4 x 10-4 s-1, K(D) = 70 pM), a remarkable finding for a noncovalent, small-molecule inhibitor of a protein receptor. BIO-1211 was also 200-fold selective for the activated form of α4β1, and it stimulated expression of ligand-induced epitopes on the integrin β1 subunit, a property consistent with occupancy of the receptor's ligand-binding site. Pretreatment of allergic sheep with a 3-mg nebulized dose of BIO-1211 inhibited early and late airway responses following antigen challenge and prevented development of nonspecific airway hyperresponsiveness to carbachol. These results show that highly selective and potent small- molecule antagonists can be identified to integrins with primary specificity for peptide domains other than Arg-Gly-Asp (RGD); they confirm the generality of integrins as small molecule targets; and they validate α4β1 as a therapeutic target for asthma.
LLP2A-BISPHOSPHONATE CONJUGATES FOR OSTEOPOROSIS TREATMENT
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Paragraph 0191, (2013/03/28)
The present invention provides compounds and pharmaceutical compositions of a peptidomimetic ligand, e.g. LLP2A, conjugated with a bisphosphonate drug, e.g. Alendronate. The compounds and pharmaceutical compositions of the present invention are useful in
Non-peptidyl inhibitors of VLA-4 dependent cell binding useful in treating inflammatory, autoimmune, and respiratory diseases
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, (2008/06/13)
Compounds of Formula (1.0.0): are described wherein A is for example aryl, heteroaryl or heterocyclyl, Y is preferably —C(═O)—; B is independently selected from a group of moieties, the most preferred of which are those of partial Formulas (1.1.2) and (1.1.6): and E is a single bond; oxygen; 1,1-cyclopropyl; C(CH3)2; CF2; or a bridging moiety of partial Formula (1.9.0): where R1ais hydrogen when R1has the meaning of a mono-valent substituent; and R1ais a single bond when R1has the meaning of a di-valent substituent. Said compounds are useful in methods of treating or preventing an inflammatory, autoimmune or respiratory diseases by inhibiting cell adhesion and consequent or associated pathogenic processes subsequently mediated by VLA-4.