Discovery and evaluation of potent, tyrosine-based α4β1 integrin antagonists

Author:

Archibald Sarah C.,Head John C.,Gozzard Neil,Howat David W.,Parton Ted A.H.,Porter John R.,Robinson Martyn K.,Shock Anthony,Warrellow Graham J.,Abraham William M.

Publisher

Elsevier BV

Subject

Organic Chemistry,Clinical Biochemistry,Drug Discovery,Pharmaceutical Science,Molecular Biology,Molecular Medicine,Biochemistry

Reference7 articles.

1. For recent reviews see (a) M. Lobb, R. R.; Adams, S. P. Exp. Opin. Invest. Drugs 1999, 8, 935. (b) Zimmerman, C. N. Exp. Opin. Ther. Patents 1999, 9, 129

2. (a) Bochner, B. S. In Cell Adhesion Molecules and Matrix Proteins: Role in Health and Diseases: Mousa, A. S., Ed.; Springer-Verlag and R. G. Landes Co., 1998; pp 113–131. (b) Elices, M. J. In Cell Adhesion Molecules and Matrix Proteins: Role in Health and Diseases: Mousa A. S., Ed.; Springer-Verlag and R. G. Landes Co., 1998; pp 133–147.

3. Archibald, S. C.; Head J. C.; Linsley, J. M.; Porter J. R.; Robinson, M. K.; Shock, A.; Warrellow, G. J. Bioorg. Med. Chem. Lett. 2000, 10, 993.

4. α4β1 (from HL60 lysate) was immobilised on a plate with a non-blocking anti-β1 antibody (TS2/16). The test compounds were titrated into a solution of 2-domain VCAM-Fc-Ig in a separate plate and added to the wells. The assay was carried out in TBS, 1% BSA, 1 mM MnCl2, 0.1% Tween. After incubation for 2 h at room temperature the plates were washed and residual VCAM visualised with peroxidase coupled anti-human Fc.

5. A Jurkat cell line expressing α4β1 was incubated at 37°C for 30 min with human 2-domain VCAM-1-FC immobilised on a plate with anti-human FC in the presence of the test compounds. The plates were washed and residual cells were stained with Rose Bengal.

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