| Autor: |
Brady, S. F., Stauffer, K. J., Lumma, W. C., Smith, G. M., Ramjit, H. G., Lewis, S. D., Lucas, B. J., Gardell, S. J., Lyle, E. A., Appleby, S. D., Cook, J. J., Holahan, M. A., Stranieri, M. T., Lynch, J. J., Jr., Lin, J. H., Chen, I.-W., Vastag, K., Naylor-Olsen, A. M., Vacca, J. P. |
| Zdroj: |
Journal of Medicinal Chemistry; January 29, 1998, Vol. 41 Issue: 3 p401-406, 6p |
| Abstrakt: |
Early studies in these laboratories of peptidomimetic structures containing a basic P1 moiety led to the highly potent and selective thrombin inhibitors 2 (Ki = 5.0 nM) and 3 (Ki = 0.1 nM). However, neither attains significant blood levels upon oral administration to rats and dogs. With the aim of improving pharmacokinetic properties via a more diverse database, we devised a resin-based route for the synthesis of analogues of these structures in which the P3 residue is replaced with a range of lipophilic carboxylic amides. Assembly proceeds from the common P2−P1 template 7 linked via an acid-labile carbamate to a polystyrene support. Application of the methodology in a repetitive fashion afforded several interesting analogues out of a collection of some 200 compounds. Among the most potent of the group, N-(9-hydroxy-9-fluorenecarboxy)prolyl trans-4-aminocyclohexylmethyl amide (L-372,460 8, Ki = 1.5 nM), in addition to being fully efficacious in a rat model of arterial thrombosis at an infusion rate of 10 μg/kg/min, exhibits oral bioavailability of 74% in dogs, and oral bioavailability of 39% in monkeys with a serum half-life of just under 4 h. On the basis of its favorable biological properties, inhibitor 8 has been subject to further evaluation as a possible treatment for thrombogenic disorders. |
| Databáze: |
Supplemental Index |
| Externí odkaz: |
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