Titre du document / Document title

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

Auteur(s) / Author(s)

MYLARI Banavara L. ⁽¹⁾ ; ARMENTO Sandra J. ⁽¹⁾ ; BEEBE David A. ⁽¹⁾ ; CONN Edward L. ⁽¹⁾ ; COUTCHER James B. ⁽¹⁾ ; DINA Michael S. ⁽¹⁾ ; O'GORMAN Melissa T. ⁽¹⁾ ; LINHARES Michael C. ⁽¹⁾ ; MARTIN William H. ⁽¹⁾ ; OATES Peter J. ⁽¹⁾ ; TESS David A. ⁽¹⁾ ; WITHBROE Gregory J. ⁽¹⁾ ; ZEMBROWSKI William J. ⁽¹⁾ ;

Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)

⁽¹⁾ Pfizer Global Research and Development, Pfizer Inc, Groton, Connecticut 06340, ETATS-UNIS

Résumé / Abstract

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, 81, 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).

Revue / Journal Title

Journal of medicinal chemistry   ISSN 0022-2623   CODEN JMCMAR 

Source / Source

2005, vol. 48, n^o20, pp. 6326-6339 [14 page(s) (article)] (43 ref.)

Langue / Language

Anglais

Editeur / Publisher

American Chemical Society, Washington, DC, ETATS-UNIS  (1963) (Revue)

Mots-clés anglais / English Keywords

Endocrinopathy ; Chlorine Organic compounds ; Vertebrata ; Mammalia ; Rodentia ; Enzyme ; Oxidoreductases ; Pharmacokinetics ; Animal ; Experimental disease ; Sciatic nerve ; Eye ; Benzene derivatives ; Six membered ring ; Sulfone ; Nitrogen heterocycle ; In vitro ; Complication ; Pyridazine derivatives ; Organic chlorine compounds ; Prevention ; Rat ; In vivo ; Diabetes mellitus ; Bioavailability ; Oral administration ; Enzyme inhibitor ; Aldehyde reductase ; Chemical synthesis ; Structure activity relation ;

Mots-clés français / French Keywords

Endocrinopathie ; Chlore Composé organique ; Vertebrata ; Mammalia ; Rodentia ; Enzyme ; Oxidoreductases ; Imidazolidine dérivé ; Pyridazin-3-one(6-[5-chloro-3-méthylbenzofurane-2-sulfonyl]) ; Inhibiteur aldose reductase ; Pharmacocinétique ; Animal ; Pathologie expérimentale ; Nerf sciatique ; Oeil ; Benzène dérivé ; Cycle 6 chaînons ; Sulfone ; Hétérocycle azote ; In vitro ; Complication ; Pyridazine dérivé ; Chlore composé organique ; Prévention ; Rat ; In vivo ; Diabète ; Biodisponibilité ; Voie orale ; Inhibiteur enzyme ; Aldehyde reductase ; Synthèse chimique ; Relation structure activité ;

Mots-clés espagnols / Spanish Keywords

Endocrinopatía ; Cloro Compuesto orgánico ; Vertebrata ; Mammalia ; Rodentia ; Enzima ; Oxidoreductases ; Farmacocinética ; Animal ; Patología experimental ; Nervio ciático ; Ojo ; Benceno derivado ; Ciclo 6 eslabones ; Sulfona ; Heterociclo nitrógeno ; In vitro ; Complicación ; Piridazina derivado ; Prevención ; Rata ; In vivo ; Diabetes ; Biodisponibilidad ; Vía oral ; Inhibidor enzima ; Aldehyde reductase ; Síntesis química ; Relación estructura actividad ;

Localisation / Location

INIST-CNRS, Cote INIST : 9165, 35400013207007.0170