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

Bioorganic and Medicinal Chemistry Letters

Volumn 10, Issue 9, 2000, Pages 997-999

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

^a UCB PHARMA   (Belgium)

^b MOUNT SINAI MEDICAL CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

METHACHOLINE; N ACETYL DTHIOPROLINE L TYROSINE; TYROSINE DERIVATIVE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; AREA UNDER THE CURVE; ARTICLE; DRUG DESIGN; DRUG POTENCY; DRUG SCREENING; DRUG SYNTHESIS; NONHUMAN; RESPIRATORY TRACT INFLAMMATION; STEREOCHEMISTRY; STRUCTURE ACTIVITY RELATION; STRUCTURE ANALYSIS;

ANIMALS; BRONCHIAL HYPERREACTIVITY; HALF-LIFE; INTEGRIN ALPHA4BETA1; INTEGRINS; INTERLEUKIN-8; METHACHOLINE CHLORIDE; PARASYMPATHOMIMETICS; PROTEIN BINDING; RATS; RECEPTORS, LYMPHOCYTE HOMING; SHEEP; STRUCTURE-ACTIVITY RELATIONSHIP; TYROSINE; VASCULAR CELL ADHESION MOLECULE-1;

ANIMALIA; BRONCHUS;

EID: 17144433994     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(00)00147-5     Document Type: Article

References (10)

1. For recent reviews see (a) M. Lobb, R. R.; Adams, S. P. Exp. Opin. Invest. Drugs 1999, 8, 935.
2. (b) Zimmerman, C. N. Exp. Opin. Ther. Patents 1999, 9, 129.
3. (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.
4. (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.
5. 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.
6. 2, 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.
7. 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.
8. Test substances were incubated in rat plasma at room temperature at initial concentrations of 10, 1 and 0.1 μM. After initial mixing and at several timepoints, 50 μL aliquots were taken and added to 200 μL acetonitrile. An internal standard was added and the extracts were analysed by LC-MS/MS. Half-lives were calculated from exponential regressions through the timepoints.
9. Abraham, W. M.; Sielczak, M. W.; Ahmed, A.; Cortes, A.; Lauredo, I. T.; Kim, J.; Pepinsky, B.; Benjamin, C. D.; Leone, D. R.; Lobb, R. R.; Weller, P. F. J. Clin. Invest. 1994, 93, 776. Abraham, W. M.; Ahmed, A.; Sielczak, M. W.; Narita, M.; Arrhenius, T.; Elices M. J. Am. J. Resp. Crit. Care. Med. 1994, 156, 776.
10. Abraham, W. M.; Sielczak, M. W.; Ahmed, A.; Cortes, A.; Lauredo, I. T.; Kim, J.; Pepinsky, B.; Benjamin, C. D.; Leone, D. R.; Lobb, R. R.; Weller, P. F. J. Clin. Invest. 1994, 93, 776. Abraham, W. M.; Ahmed, A.; Sielczak, M. W.; Narita, M.; Arrhenius, T.; Elices M. J. Am. J. Resp. Crit. Care. Med. 1994, 156, 776.