Orally-effective, long-acting sorbitol dehydrogenase inhibitors: synthesis, structure-activity relationships, and in vivo evaluations of novel heterocycle-substituted piperazino-pyrimidines
| Autor: | Day Wesley Warren, David A. Beebe, Margaret Y. Chu-Moyer, William E. Ballinger, Peter J. Oates, Banavara L. Mylari, Jiancheng Li, James B. Coutcher, Richard Berger, R. Matthew Weekly |
|---|---|
| Rok vydání: | 2002 |
| Předmět: |
Male
L-Iditol 2-Dehydrogenase Sorbitol dehydrogenase Fructose Pharmacology Piperazines Diabetes Mellitus Experimental Rats Sprague-Dawley chemistry.chemical_compound Structure-Activity Relationship Pharmacokinetics In vivo Oral administration Drug Discovery Structure–activity relationship Potency Animals Enzyme Inhibitors biology Chemistry Stereoisomerism Sciatic Nerve Rats Pyrimidines Biochemistry Enzyme inhibitor Chronic Disease biology.protein Molecular Medicine |
| Zdroj: | Journal of medicinal chemistry. 45(2) |
| ISSN: | 0022-2623 |
| Popis: | Optimization of a previously disclosed sorbitol dehydrogenase inhibitor (SDI, II) for potency and duration of action was achieved by replacing the metabolically labile N,N-dimethylsulfamoyl group with a variety of heterocycles. Specifically, this effort led to a series of novel, in vitro potent SDIs with longer serum half-lives and acceptable in vivo activity in acutely diabetic rats (e.g., 62, 67, and 69). However, the desired in vivo potency in chronically diabetic rats, ED(90)or = 5 mg/kg/day, was achieved only through further modification of the piperazine linker. Several members of this family, including 86, showed better than the targeted potency with ED(90) values of 1-2 mg/kg/day. Compound 86 was further profiled and found to be a selective inhibitor of sorbitol dehydrogenase, with excellent pharmacodynamic/pharmacokinetic properties, demonstrating normalization of sciatic nerve fructose in a chronically diabetic rat model for approximately 17 h, when administered orally at a single dose of 2 mg/kg/day. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|