- 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
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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)-2/f-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; ED 90 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 t1/2 (26 ± 3 h).
- Mylari, Banavara L.,Armento, Sandra J.,Beebe, David A.,Conn, Edward L.,Coutcher, James B.,Dina, Michael S.,O'Gorman, Melissa T.,Linhares, Michael C.,Martin, William H.,Oates, Peter J.,Tess, David A.,Withbroe, Gregory J.,Zembrowski, William J.
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p. 6326 - 6339
(2007/10/03)
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- 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
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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, f
- Mylari, Banavara L.,Armento, Sandra J.,Beebe, David A.,Conn, Edward L.,Coutcher, James B.,Dina, Michael S.,O'Gorman, Melissa T.,Linhares, Michael C.,Martin, William H.,Oates, Peter J.,Tess, David A.,Withbroe, Gregory J.,Zembrowski, William J.
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p. 2283 - 2286
(2007/10/03)
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- NEW USE OF THE ADENOSINE ANTAGONIST
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The present method for the treatment of pancreatitis, which comprises administering an effective amount of a pyrazolopyridine compound of the following formula: STR1 wherein R 1 is lower alkyl, (substituted) aryl, or a heterocyclic group,R. sup.2 is
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