Design and synthesis of a novel family of triazine-based inhibitors of sorbitol dehydrogenase with oral activity: 1-[4-[3R,5S-dimethyl-4-(4-methyl-[1,3,5]triazin-2-yl)-piperazin-1-yl]-[1,3,5]triazin-2-yl]-(R) ethanol.
Two new templates, (R) 2-hydroxyethyl-pyridine and (R) 2-hydroxyethyl-triazine, were used to design novel sorbitol dehydrogenase inhibitors (SDIs). The design concept included spawning of these templates to function as effective ligands to the catalytic zinc within the enzyme through incorporation of optimally substituted piperazino-triazine side chains so as to accommodate the active site in the enzyme for efficient binding. This strategy resulted in orally active SDIs, which penetrate key tissues, for example, sciatic nerve of chronically diabetic rats. The latter template led to the design of the title inhibitor, 33, which normalized the elevated sciatic nerve fructose by 96% at an oral dose of 10mg/kg.
Mylari
Banavara L
BL
Pfizer Global Research and Development, Groton Laboratories, Groton, CT 06340, USA. blmylari@aol.com
Withbroe
Gregory J
GJ
Beebe
David A
DA
Brackett
Nathaniel S
NS
Conn
Edward L
EL
Coutcher
James B
JB
Oates
Peter J
PJ
Zembrowski
William J
WJ
D000284:Administration, Oral; D000818:Animals; D002384:Catalysis; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D000431:Ethanol / Q000031:analogs & derivatives*; D005632:Fructose / Q000378:metabolism; D006801:Humans; D007064:L-Iditol 2-Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D012584:Sciatic Nerve / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis* / Q000494:pharmacology; D015032:Zinc / Q000737:chemistry
C485445:1-(4-(3R,5S-dimethyl-4-(4-methyl)-(1,3,5-triazin-2-yl)-piperazin-1-yl)-(1,3,5)triazin-2-yl)-(R)-ethanol; D004791:Enzyme Inhibitors; D010879:Piperazines; D014227:Triazines; D005632:Fructose; D000431:Ethanol; D007064:L-Iditol 2-Dehydrogenase; D015032:Zinc