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

3-Guanidinopropionic acid (1, PNU-10483) has been demonstrated to both impr ove 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 tr ansporter and creatine kinase, leading to marked accumulation in muscle tis sue as the corresponding N-phosphate 4. In an effort to identify novel enti ties 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 substit ution, single atom mutations, and bioisosteric replacements for the guanidi ne and carboxylic acid. Overall, the scope of activity encompassed by the s et of new analogues proved to be exceedingly narrow. Notable exceptions dem onstrating equivalent or improved antidiabetic activity included the alpha- amino derivative 29, aminopyridine 47, isothiourea 67, and aminoguanidine 6 9. On the basis of its superior therapeutic ratio, aminoguanidine 69 was se lected for preclinical development and became the foundation for a second p hase of analogue work. Furthermore, in vitro studies demonstrated that 69 i s markedly less susceptible to phosphorylation by creatine kinase than the lead 1, suggesting that it should have less potential for accumulation in m uscle tissue than 1.