Linked Life Data

11312923

Source:http://linkedlifedata.com/resource/pubmed/id/11312923

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
8
pubmed:dateCreated
2001-4-23
pubmed:abstractText
3-Guanidinopropionic acid (1) has been demonstrated both to improve insulin sensitivity and to promote weight loss selectively from adipose tissue in animal models of non-insulin-dependent diabetes mellitus (NIDDM). However, 1 has also been shown to be a substrate for both the creatine transporter and creatine kinase, leading to marked accumulation in muscle tissue as the corresponding N-phosphate. The corresponding aminoguanidine analogue 2 was recently discovered to retain the antidiabetic activity of 1 while being markedly less susceptible to creatine-like metabolism, suggesting that it should have less potential to accumulate in muscle. Further structural modification of 2 was undertaken to investigate whether the antidiabetic potency could be augmented while maintaining resistance to creatine-like metabolism. Modifications such as alpha-alkylation, homologation, and bioisosteric replacement of the aminoguanidine all were detrimental to antidiabetic activity. However, the simple regioisomeric aminoguanidinoacetic acid 9 and diaminoguanidinoacetic acid analogue 7 were found to be equipotent to 2, leading eventually to the discovery of the significantly more potent diaminoguanidinoacetic acid regioisomers 52 and 53. Further attempts to modify the more active template represented by 52 led only to reductions in antidiabetic activity. Each of the new active analogues displayed the same resistance to creatine-like metabolism as 2. Further testing of 7, 9, and 53 in obese diabetic ob/ob mice confirmed that weight loss is induced selectively from adipose tissue, similar to the lead 1. Administration of 53 to insulin-resistant rhesus monkeys led to reductions in both fasting and post-prandial plasma glucose levels with concomitant reductions in plasma insulin levels, suggesting that the compound improved the action of endogenous insulin. Compounds 7 and 53 were selected for further preclinical development.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Apr
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
12
pubmed:volume
44
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1231-48
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed:year
2001
pubmed:articleTitle
Synthesis and biological activity of aminoguanidine and diaminoguanidine analogues of the antidiabetic/antiobesity agent 3-guanidinopropionic acid.
pubmed:affiliation
Departments of Medicinal Chemistry, Pharmacology, and Research Biostatistics, Pharmacia Corporation, 301 Henrietta Street, Kalamazoo, Michigan 49007, USA. valerie.a.vaillancourt@am.pnu.com
pubmed:publicationType
Journal Article, In Vitro