A novel series of non-carboxylic acid, non-hydantoin inhibitors of aldose reductase with potent oral activity in diabetic rat models: 6-(5-chloro-3-methylbenzofuran-2-sulfonyl)-2H-pyridazin-3-one and congeners.
Discovery of a highly selective, potent, and safe non-carboxylic acid, non-hydantoin inhibitor of aldose reductase (AR) capable of potently blocking the excess glucose flux through the polyol pathway that prevails under diabetic conditions has been a long-standing challenge. In response, we did high-throughput screening of our internal libraries of compounds and identified 6-phenylsulfonylpyridazin-2H-3-one, 8, which showed modest inhibition of AR, both in vitro and in vivo. Initial structure-activity relationships concentrated on phenyl substituents and led to 6-(2,4-dichlorophenylsulfonyl)-2H-pyridazin-3-one, 8l, which was more potent than 8, both in vitro and in vivo. Incorporation of extant literature findings with other aldose reductase inhibitors, including zopolrestat, resulted in the title inhibitor, 19m, which is one of the most potent and highly selective non-carboxylic acid, non-hydantoin inhibitors of AR yet described (IC50, 1 nM; ED90 vs sciatic nerve sorbitol and fructose, respectively, 0.8 and 4.0 mg/kg). In rats, its oral bioavailability is 98% and it has a favorable 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; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D005632:Fructose / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007908:Lens, Crystalline / Q000378:metabolism; D008297:Male; D011724:Pyridazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D012584:Sciatic Nerve / Q000187:drug effects / Q000378:metabolism; D013012:Sorbitol / Q000378:metabolism; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D007004:Hypoglycemic Agents; D011724:Pyridazines; D011994:Recombinant Proteins; D013450:Sulfones; D005632:Fructose; D013012:Sorbitol; D000449:Aldehyde Reductase; C475424:6-(5-chloro-3-methylbenzofuran-2-sulfonyl)-2H-pyridazin-3-one