| Autor: |
Pitts WJ; DuPont Pharmaceuticals Company, P.O. Box 80500, Wilmington, Delaware 19880-0500, USA., Wityak J, Smallheer JM, Tobin AE, Jetter JW, Buynitsky JS, Harlow PP, Solomon KA, Corjay MH, Mousa SA, Wexler RR, Jadhav PK |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of medicinal chemistry [J Med Chem] 2000 Jan 13; Vol. 43 (1), pp. 27-40. |
| DOI: |
10.1021/jm9900321 |
| Abstrakt: |
Starting with lead compound 2, we sought to increase the selectivity for alpha(v)beta(3)-mediated cell adhesion by examining the effects of structural changes in both the guanidine mimetic and the substituent alpha 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 pK(a)'s were potent antagonists of alpha(v)beta(3). In general, it appeared that an acylated 2-aminoimidazole guanidine mimetic imparted excellent selectivity for alpha(v)beta(3)-mediated adhesion versus alpha(IIb)beta(3)-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 alpha-substituent was required for potent activity and that 2,6-disubstituted arylsulfonamides were optimal. In addition, the selective alpha(v)beta(3) antagonist 3h was found to be a potent inhibitor of alpha(v)beta(3)-mediated cell migration. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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