PMID: 11312922Apr 21, 2001Paper

Synthesis and biological activity of analogues of the antidiabetic/antiobesity agent 3-guanidinopropionic acid: discovery of a novel aminoguanidinoacetic acid antidiabetic agent

Journal of Medicinal Chemistry
S D LarsenJ H Yu

Abstract

3-Guanidinopropionic acid (1, PNU-10483) has been demonstrated to both 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 4. In an effort to identify novel entities that maintain antidiabetic potency without susceptibility to creatine-like metabolism, an analogue program was undertaken to explore the effects of various structural modifications, including homologation, simple substitution, single atom mutations, and bioisosteric replacements for the guanidine and carboxylic acid. Overall, the scope of activity encompassed by the set of new analogues proved to be exceedingly narrow. Notable exceptions demonstrating equivalent or improved antidiabetic activity included the alpha-amino derivative 29, aminopyridine 47, isothiourea 67, and aminoguanidine 69. On the basis of its superior therapeutic ratio, aminoguanidine 69 was selected for preclinical development and became the foundation for a second phase of analogue work. Furthermore, in vitro st...Continue Reading

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Citations

Jul 27, 2001·Drug Discovery Today·D BarloccoD Tranter
Nov 23, 2013·Expert Opinion on Drug Discovery·Muhammad Khawar RaufAmin Badshah
Mar 17, 2011·Neurobiology of Disease·Tamas L HorvathZane B Andrews
Jun 25, 2016·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Giovanna Bosica, Roderick Abdilla
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Dec 21, 2005·Journal of Computational Chemistry·Prasad V Bharatam, Pansy Iqbal
Jul 3, 2013·Journal of Clinical Imaging Science·Rebecca WuDouglas S Katz
Jul 10, 2019·Dalton Transactions : an International Journal of Inorganic Chemistry·Jing XiangTai-Chu Lau
Dec 9, 2004·Chemical Reviews·Luigi AurelioAndrew B Hughes
Aug 12, 2004·Journal of the American Chemical Society·Hui-Ting ChenEric E Simanek
May 9, 2009·Journal of Medicinal Chemistry·Geoffrey D CoxonRoger D Waigh
Apr 28, 2004·Bioorganic & Medicinal Chemistry Letters· FarhanullahVishnu Ji Ram
Oct 6, 2005·Bioorganic & Medicinal Chemistry Letters·Helen L BirchSophie C Williams

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