Linked Life Data

8027987

Source:http://linkedlifedata.com/resource/pubmed/id/8027987

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
13
pubmed:dateCreated
1994-8-9
pubmed:abstractText
The isoquinoline-1,3-dione framework featured in our clinical candidate (1) and its congener was used as the template in the design of several new series of aldose reductase inhibitors (ARIs). These series included N'-substituted spirosuccinimide, spiropyridazine, spiroazetidine, and acetic acid analogues. Compounds within these series were evaluated in vitro for their ability to inhibit glyceraldehyde reduction by bovine lens aldose reductase and in vivo by their ability to inhibit galactitol accumulation in the lens and sciatic nerve of galactose-fed rats. The N'-amino- and N'-alkyl-substituted spiro[isoquinoline-4(1H),3'-pyrrolidine]-1,2',3,5'(2H)- tetrones 6 exhibited high oral potency, even though they were devoid of any intrinsic activity for the aldose reductase enzyme. Similar results were observed for the closely related spiropyridazines 8. Both of these groups are also considered to be prodrugs since they exhibited good oral potency, even though they were devoid of any intrinsic activity for the aldose reductase enzyme. In contrast, the isoquinoline-1,3-dione acetic acids 9 exhibited very high intrinsic activity for the aldose reductase enzyme, although minimal or no in vivo activity. The absence of in vivo activity for some of these compounds may be due to poor tissue penetration. In support of this suggestion, the more lipophilic acetyl alkyl carbamate derivatives of these isoquinoline-1,3-dione acetic acids, exhibited enhanced oral potency. The spiroazetidines 7 exhibited good activity for the aldoe reductase enzyme in both the in vitro and in vivo assays. The findings of this study demonstrate the utility of the isoquinoline-1,3-dione framework, as a versatile template for the design of divese series of potent ARIs.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
24
pubmed:volume
37
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
2059-70
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed:year
1994
pubmed:articleTitle
N-substituted spirosuccinimide, spiropyridazine, spiroazetidine, and acetic acid aldose reductase inhibitors derived from isoquinoline-1,3-diones. 2.
pubmed:affiliation
Wyeth-Ayerst Research Inc., Princeton, New Jersey 08543-8000.
pubmed:publicationType
Journal Article, In Vitro