title: 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.
abstract: 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).
authors.affiliation: Pfizer Global Research and Development, Pfizer Inc., Groton, Connecticut 06340, USA. blmylari@aol.com
authors.forename: Banavara L
authors.initials: BL
authors.lastname: Mylari
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Armento
authors.forename: David A
authors.initials: DA
authors.lastname: Beebe
authors.forename: Edward L
authors.initials: EL
authors.lastname: Conn
authors.forename: James B
authors.initials: JB
authors.lastname: Coutcher
authors.forename: Michael S
authors.initials: MS
authors.lastname: Dina
authors.forename: Melissa T
authors.initials: MT
authors.lastname: O'Gorman
authors.forename: Michael C
authors.initials: MC
authors.lastname: Linhares
authors.forename: William H
authors.initials: WH
authors.lastname: Martin
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Oates
authors.forename: David A
authors.initials: DA
authors.lastname: Tess
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Withbroe
authors.forename: William J
authors.initials: WJ
authors.lastname: Zembrowski
mesh_terms: 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
chemical_list: 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