400786-01-8Relevant academic research and scientific papers
Orally-effective, long-acting sorbitol dehydrogenase inhibitors: Synthesis, structure - Activity relationships, and in vivo evaluations of novel heterocycle-substituted piperazino-pyrimidines
Chu-Moyer, Margaret Y.,Ballinger, William E.,Beebe, David A.,Berger, Richard,Coutcher, James B.,Day, Wesley W.,Li, Jiancheng,Mylari, Banavara L.,Oates, Peter J.,Weekly, R. Matthew
, p. 511 - 528 (2007/10/03)
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, ED90 ≤ 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 ED90 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 ～17 h, when administered orally at a single dose of 2 mg/kg/day.
