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.
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.
Mylari
Banavara L
BL
Pfizer Global Research and Development, Groton Laboratories, Groton, Connecticut 06340, USA. blmylari@aol.com
Oates
Peter J
PJ
Zembrowski
William J
WJ
Beebe
David A
DA
Conn
Edward L
EL
Coutcher
James B
JB
O'Gorman
Melissa T
MT
Linhares
Michael C
MC
Withbroe
Gregory J
GJ
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
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