| Autor: |
Pitts, W. J., Wityak, J., Smallheer, J. M., Tobin, A. E., Jetter, J. W., Buynitsky, J. S., Harlow, P. P., Solomon, K. A., Corjay, M. H., Mousa, S. A., Wexler, R. R., Jadhav, P. K. |
| Zdroj: |
Journal of Medicinal Chemistry; January 13, 2000, Vol. 43 Issue: 1 p27-40, 14p |
| Abstrakt: |
Starting with lead compound 2, we sought to increase the selectivity for αvβ3-mediated cell adhesion by examining the effects of structural changes in both the guanidine mimetic and the substituent α to the carboxylate. To prepare some of the desired aminoimidazoles, a novel reductive amination utilizing a trityl-protected aminoimidazole was developed. It was found that guanidine mimetics with a wide range of pKa's were potent antagonists of αvβ3. In general, it appeared that an acylated 2-aminoimidazole guanidine mimetic imparted excellent selectivity for αvβ3-mediated adhesion versus αIIbβ3-mediated platelet aggregation, with selectivity of approximately 3 orders of magnitude observed for compounds 3g and 3h. It was also found in this series that the α-substituent was required for potent activity and that 2,6-disubstituted arylsulfonamides were optimal. In addition, the selective αvβ3 antagonist 3h was found to be a potent inhibitor of αvβ3-mediated cell migration. |
| Databáze: |
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