A highly selective, non-hydantoin, non-carboxylic acid inhibitor of aldose reductase with potent oral activity in diabetic rat models: 6-(5-chloro-3-methylbenzofuran- 2-sulfonyl)-2-H-pyridazin-3-one.
We report here on the discovery path that led to a structurally unprecedented non-hydantoin, non-carboxylic acid aldose reductase inhibitor, 24, which shows remarkably potent oral activity in normalizing elevated sorbitol levels and, more significantly, fructose levels in the sciatic nerve of chronically diabetic rats, with ED(90) values of 0.8 and 3 mpk, respectively. It is well absorbed in rats (oral bioavailability, 98%) and has a long plasma t(1/2) (26 +/- 3 h).
Mylari
Banavara L
BL
Pfizer Global Research and Development, Pfizer Inc., Groton, Connecticut 06340, USA. blmylari@aol.com
Armento
Sandra J
SJ
Beebe
David A
DA
Conn
Edward L
EL
Coutcher
James B
JB
Dina
Michael S
MS
O'Gorman
Melissa T
MT
Linhares
Michael C
MC
Martin
William H
WH
Oates
Peter J
PJ
Tess
David A
DA
Withbroe
Gregory J
GJ
Zembrowski
William J
WJ
D000284:Administration, Oral; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000818:Animals; D001682:Biological Availability; D018938:Caco-2 Cells; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005632:Fructose / Q000097:blood; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007908:Lens, Crystalline / Q000187:drug effects / Q000201:enzymology; D010539:Permeability; D011724:Pyridazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D012584:Sciatic Nerve / Q000187:drug effects / Q000201:enzymology; D013012:Sorbitol / Q000097:blood; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D011724:Pyridazines; D013450:Sulfones; D005632:Fructose; D013012:Sorbitol; D000449:Aldehyde Reductase; C475424:6-(5-chloro-3-methylbenzofuran-2-sulfonyl)-2H-pyridazin-3-one