title: Sorbitol dehydrogenase inhibitors (SDIs): a new potent, enantiomeric SDI, 4-[2-1R-hydroxy-ethyl)-pyrimidin-4-yl]piperazine-1-sulfonic acid dimethylamide.
abstract: We report here on our medicinal chemistry and pharmacology efforts to provide a potent sorbitol dehydrogenase inhibitor (SDI) as a tool to probe a recently disclosed hypothesis centered on the role of sorbitol dehydrogenase (SDH) in the second step of the polyol pathway, under conditions of high glucose flux. Starting from a weak literature lead, 2, and through newly developed structure-activity relationships, we have designed and executed an unambiguous synthesis of enantiomeric SDI, 6, which is at least 10x more potent than 2. Also, 6 potently inhibits SDH in streptozotocin-diabetic rat sciatic nerve. We have described an expedient synthesis of a key building template, 33, for future research in the SDI area that may facilitate the discovery of even more potent SDIs with longer duration of action in vivo.
authors.affiliation: Department of Cardiovascular and Metabolic Diseases, Pfizer Global Research & Development, Pfizer Inc., Groton, Connecticut 06340, USA. lmylari@home.com
authors.forename: B L
authors.initials: BL
authors.lastname: Mylari
authors.forename: P J
authors.initials: PJ
authors.lastname: Oates
authors.forename: D A
authors.initials: DA
authors.lastname: Beebe
authors.forename: N S
authors.initials: NS
authors.lastname: Brackett
authors.forename: J B
authors.initials: JB
authors.lastname: Coutcher
authors.forename: M S
authors.initials: MS
authors.lastname: Dina
authors.forename: W J
authors.initials: WJ
authors.lastname: Zembrowski
mesh_terms: D000284:Administration, Oral; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D005632:Fructose / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D006801:Humans; D007064:L-Iditol 2-Dehydrogenase / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D012584:Sciatic Nerve / Q000378:metabolism; D013237:Stereoisomerism; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D014018:Tissue Distribution
chemical_list: C433816:4-(2-hydroxyethylpyrimidin-1-yl)piperazine-1-sulfonic acid dimethylamide; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D005632:Fructose; D007064:L-Iditol 2-Dehydrogenase