title: Orally-effective, long-acting sorbitol dehydrogenase inhibitors: synthesis, structure-activity relationships, and in vivo evaluations of novel heterocycle-substituted piperazino-pyrimidines.
abstract: 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.
authors.affiliation: 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
authors.forename: Margaret Y
authors.initials: MY
authors.lastname: Chu-Moyer
authors.forename: William E
authors.initials: WE
authors.lastname: Ballinger
authors.forename: David A
authors.initials: DA
authors.lastname: Beebe
authors.forename: Richard
authors.initials: R
authors.lastname: Berger
authors.forename: James B
authors.initials: JB
authors.lastname: Coutcher
authors.forename: Wesley W
authors.initials: WW
authors.lastname: Day
authors.forename: Jiancheng
authors.initials: J
authors.lastname: Li
authors.forename: Banavara L
authors.initials: BL
authors.lastname: Mylari
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Oates
authors.forename: R Matthew
authors.initials: RM
authors.lastname: Weekly
mesh_terms: 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
chemical_list: 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