title: A sorbitol dehydrogenase inhibitor of exceptional in vivo potency with a long duration of action: 1-(R)-[4-[4-(4,6-dimethyl[1,3,5]triazin-2-yl)- 2R,6S-dimethylpiperazin-1-yl]pyrimidin-2- yl]ethanol.
abstract: We report here a novel sorbitol dehydrogenase inhibitor, 16, that shows very high oral potency (50 microg/kg) in normalizing elevated fructose levels in the sciatic nerve of chronically diabetic rats and sustained duration of action (>24 h). Furthermore, 16 shows attractive pharmaceutical properties, including good solubility in simulated human gastric fluid, excellent Caco-2 Papp, moderate lipophilicity, and metabolic stability for achieving good oral absorption and long duration of action.
authors.affiliation: Pfizer Global Research and Development, Groton Laboratories, Groton, Connecticut 06340, USA. blmylari@aol.com
authors.forename: Banavara L
authors.initials: BL
authors.lastname: Mylari
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Oates
authors.forename: William J
authors.initials: WJ
authors.lastname: Zembrowski
authors.forename: David A
authors.initials: DA
authors.lastname: Beebe
authors.forename: Edward L
authors.initials: EL
authors.lastname: Conn
authors.forename: James B
authors.initials: JB
authors.lastname: Coutcher
authors.forename: Melissa T
authors.initials: MT
authors.lastname: O'Gorman
authors.forename: Michael C
authors.initials: MC
authors.lastname: Linhares
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Withbroe
mesh_terms: D000284:Administration, Oral; D000818:Animals; D018938:Caco-2 Cells; D003920:Diabetes Mellitus / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005632:Fructose / Q000378:metabolism; D006801:Humans; D007064:L-Iditol 2-Dehydrogenase / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D012584:Sciatic Nerve / Q000187:drug effects / Q000378:metabolism; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C466637:1-(4-(4-(4,6-dimethyl(1,3,5)triazin-2-yl)2,6,-dimethylpiperazin-1-yl)pyrimidin-2-yl)ethanol; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D014227:Triazines; D005632:Fructose; D007064:L-Iditol 2-Dehydrogenase