Document Detail

Novel spirosuccinimide aldose reductase inhibitors derived from isoquinoline-1,3-diones: 2-[(4-bromo-2-fluorophenyl)methyl]-6- fluorospiro[isoquinoline-4(1H),3'-pyrrolidine]-1,2',3,5'(2H)-tetrone and congeners. 1.
MedLine Citation:
PMID:  8027986     Owner:  NLM     Status:  MEDLINE    
The high concentrations of plasma glucose formed during diabetic hyperglycemia rapidly translate into high levels of glucose in tissues where glucose uptake is independent of insulin. In these tissues that include the lens, retina, nerve, and kidney, this excess glucose enters the sorbitol (polyol) pathway. The first enzyme in this pathway, aldose reductase, reduces glucose to sorbitol. The diabetes-induced increased flux of glucose through the polyol pathway is believed to play an important role in the development of certain chronic complications of diabetes mellitus. Compounds that inhibit aldose reductase activity and block the flux of glucose through the polyol pathway prevent the development of neuropathy and nephropathy in diabetic animals and interrupt the progression of neuropathy in diabetic patients. Here we describe the preparation and characterization of novel aldose reductase inhibitors. These spiro[isoquinoline-4(1H),3'-pyrrolidine]-1,2',3,5'-(2H)-tetrones, based on the isoquinoline-1,3-dione framework, were evaluated in vitro for their ability to inhibit glyceraldehyde reduction, using a partially purified bovine lens aldose reductase preparation, and in vivo for their ability to inhibit galactitol accumulation in the lens and sciatic nerve of galactose-fed rats. Substitution at the N-2 position of the isoquinoline-1,3-dione framework with diverse structural substituents (i.e., aralkyl, benzothiazolylmethyl, methyl) produced several excellent series of ARIs. Optimization of these new series of spirosuccinimides through structure-activity relationship (SAR) studies, including analogy from other drug series (ponalrestat, zopolrestat), led to the design of the clinical candidate 2-[(4-bromo-2-fluorophenyl)methyl]-6-fluorospiro[isoquinoline-4(1H ),3'- pyrrolidine]-1,2',3,5'(2H)-tetrone (41). Compound 41 exhibited exceptional oral potency in two animal models of diabetic complications, the 14-day galactose-fed and streptozocin-induced diabetic rats, with ED50 values for the sciatic nerve of 0.1 and 0.09 mg/kg/day, respectively. Both enantiomeric forms of 41 exhibited similar inhibitory activity in both in vitro and in vivo assays possibly due to their rapid interconversion. In an ex vivo experiment, the pharmacodynamic effect of 41 in the plasma of rats and dogs, after a single dose, appeared to be comparable to that of tolrestat.
M S Malamas; T C Hohman; J Millen
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Publication Detail:
Type:  In Vitro; Journal Article    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  37     ISSN:  0022-2623     ISO Abbreviation:  J. Med. Chem.     Publication Date:  1994 Jun 
Date Detail:
Created Date:  1994-08-09     Completed Date:  1994-08-09     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  2043-58     Citation Subset:  IM    
Wyeth-Ayerst Research, Inc., Princeton, New Jersey 08543-8000.
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MeSH Terms
Aldehyde Reductase / antagonists & inhibitors*,  blood
Blood Glucose / metabolism
Diabetes Mellitus, Experimental / drug therapy*,  metabolism
Drug Evaluation, Preclinical
Erythrocytes / enzymology
Galactitol / metabolism
Galactosemias / drug therapy,  metabolism
Glyceraldehyde / metabolism
Isoquinolines / chemical synthesis,  chemistry,  pharmacology*,  therapeutic use
Lens, Crystalline / drug effects,  metabolism
Rats, Sprague-Dawley
Sciatic Nerve / drug effects,  metabolism
Spiro Compounds / chemical synthesis,  chemistry,  pharmacology*,  therapeutic use
Reg. No./Substance:
0/Blood Glucose; 0/Isoquinolines; 0/Spiro Compounds; 155683-53-7/2-((4-bromo-2-fluorophenyl)methyl)-6-fluorospiro(isoquinoline-4(1H),3'-pyrrolidine)-1,2',3,5'(2H)-tetrone; 367-47-5/Glyceraldehyde; 608-66-2/Galactitol; EC Reductase

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