Sorbitol dehydrogenase inhibitors (SDIs): a new potent, enantiomeric SDI, 4-[2-1R-hydroxy-ethyl)-pyrimidin-4-yl]piperazine-1-sulfonic acid dimethylamide.
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.
Mylari
B L
BL
Department of Cardiovascular and Metabolic Diseases, Pfizer Global Research & Development, Pfizer Inc., Groton, Connecticut 06340, USA. lmylari@home.com
Oates
P J
PJ
Beebe
D A
DA
Brackett
N S
NS
Coutcher
J B
JB
Dina
M S
MS
Zembrowski
W J
WJ
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
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