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, 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).
Subject(s)
Aldehyde Reductase/antagonists & inhibitors , Aldehyde Reductase/chemistry , Diabetes Mellitus, Experimental/drug therapy , Hypoglycemic Agents/chemical synthesis , Pyridazines/chemical synthesis , Sulfones/chemical synthesis , Administration, Oral , Animals , Biological Availability , Caco-2 Cells , Fructose/metabolism , Humans , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Lens, Crystalline/metabolism , Male , Pyridazines/chemistry , Pyridazines/pharmacology , Rats , Rats, Sprague-Dawley , Recombinant Proteins/antagonists & inhibitors , Sciatic Nerve/drug effects , Sciatic Nerve/metabolism , Sorbitol/metabolism , Structure-Activity Relationship , Sulfones/chemistry , Sulfones/pharmacologyABSTRACT
Two new templates, (R) 2-hydroxyethyl-pyridine and (R) 2-hydroxyethyl-triazine, were used to design novel sorbitol dehydrogenase inhibitors (SDIs). The design concept included spawning of these templates to function as effective ligands to the catalytic zinc within the enzyme through incorporation of optimally substituted piperazino-triazine side chains so as to accommodate the active site in the enzyme for efficient binding. This strategy resulted in orally active SDIs, which penetrate key tissues, for example, sciatic nerve of chronically diabetic rats. The latter template led to the design of the title inhibitor, 33, which normalized the elevated sciatic nerve fructose by 96% at an oral dose of 10mg/kg.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Ethanol/analogs & derivatives , L-Iditol 2-Dehydrogenase/antagonists & inhibitors , Piperazines/chemical synthesis , Triazines/chemical synthesis , Administration, Oral , Animals , Catalysis , Diabetes Mellitus, Experimental/metabolism , Drug Design , Enzyme Inhibitors/pharmacology , Fructose/metabolism , Humans , L-Iditol 2-Dehydrogenase/metabolism , Piperazines/pharmacology , Rats , Sciatic Nerve/drug effects , Sciatic Nerve/metabolism , Structure-Activity Relationship , Triazines/pharmacology , Zinc/chemistryABSTRACT
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).
Subject(s)
Aldehyde Reductase/antagonists & inhibitors , Diabetes Mellitus, Experimental/metabolism , Enzyme Inhibitors/chemical synthesis , Hypoglycemic Agents/chemical synthesis , Pyridazines/chemical synthesis , Sulfones/chemical synthesis , Administration, Oral , Aldehyde Reductase/chemistry , Animals , Biological Availability , Caco-2 Cells , Combinatorial Chemistry Techniques , Crystallography, X-Ray , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Fructose/blood , Humans , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Lens, Crystalline/drug effects , Lens, Crystalline/enzymology , Permeability , Pyridazines/chemistry , Pyridazines/pharmacology , Rats , Sciatic Nerve/drug effects , Sciatic Nerve/enzymology , Sorbitol/blood , Structure-Activity Relationship , Sulfones/chemistry , Sulfones/pharmacologyABSTRACT
We report here a novel sorbitol dehydrogenase inhibitor, 16, that shows very high oral potency (50 microg/kg) in normalizing elevated fructose levels in the sciatic nerve of chronically diabetic rats and sustained duration of action (>24 h). Furthermore, 16 shows attractive pharmaceutical properties, including good solubility in simulated human gastric fluid, excellent Caco-2 Papp, moderate lipophilicity, and metabolic stability for achieving good oral absorption and long duration of action.