Orally-effective, long-acting sorbitol dehydrogenase inhibitors: synthesis, structure-activity relationships, and in vivo evaluations of novel heterocycle-substituted piperazino-pyrimidines.
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.
Chu-Moyer
Margaret Y
MY
Department of Medicinal Chemistry, Pfizer Global Research and Development, Groton Laboratories MS 8220-3095, Eastern Point Road, Groton, Connecticut 06340, USA. margaret_y_cho@groton.pfizer.com
Ballinger
William E
WE
Beebe
David A
DA
Berger
Richard
R
Coutcher
James B
JB
Day
Wesley W
WW
Li
Jiancheng
J
Mylari
Banavara L
BL
Oates
Peter J
PJ
Weekly
R Matthew
RM
D000818:Animals; D002908:Chronic Disease; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005632:Fructose / Q000378:metabolism; D007064:L-Iditol 2-Dehydrogenase / Q000037:antagonists & inhibitors*; D008297:Male; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C446061:1-(4-(4-(2-(1-hydroxyethyl)pyrimidin-4-yl)-2,6-dimethylpiperazin-1-yl)pyrimidin-2-yl)ethanol; D004791:Enzyme Inhibitors; D010879:Piperazines; D011743:Pyrimidines; D005632:Fructose; D007064:L-Iditol 2-Dehydrogenase