| Autor: |
Kasibhatla SR; Metabasis Therapeutics Inc., San Diego, California 92121, USA., Bookser BC, Appleman JR, Probst G, Xiao W, Fujitaki JM, Erion MD |
| Jazyk: |
angličtina |
| Zdroj: |
Advances in experimental medicine and biology [Adv Exp Med Biol] 1998; Vol. 431, pp. 849-52. |
| DOI: |
10.1007/978-1-4615-5381-6_163 |
| Abstrakt: |
Structure-activity studies have been performed to optimize the potency of this novel series of AMPDA inhibitors. Conformational rigidification of the N-3 sidechain resulted in substantial effect on the potency. Addition of the hydrophobic groups provided further benefit. The most potent compound identified, 4g (Ki = 3 nM), bears little structural resemblance to AMP and exhibits a remarkable improvement (10(3) and 10(5)) in binding affinity relative to the original lead and AMP, respectively. The application of prodrug strategy achieved a large improvement (benzyl ester 5d) in oral bioavailability, resulting in compounds that should be useful in evaluating the role of AMPDA in normo- and pathophysiological states. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
|
