Synthesis and biological activity of aminoguanidine and diaminoguanidine analogues of the antidiabetic/antiobesity agent 3-guanidinopropionic acid

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 a nd 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 ma rkedly less susceptible to creatine-like metabolism, suggesting that it sho uld have less potential to accumulate in muscle. Further structural modific ation of 2 was undertaken to investigate whether the antidiabetic potency c ould be augmented while maintaining resistance to creatine-like metabolism. Modifications such as a-alkylation, homologation, and bioisosteric replace ment of the aminoguanidine all were detrimental to antidiabetic activity. H owever, the simple regioisomeric aminoguanidinoacetic acid 9 and diaminogua nidinoacetic acid-analogue 7 were found to be equipotent to 2, leading even tually to the discovery of the significantly more potent diaminoguanidinoac etic acid regioisomers 52 and 53. Further attempts to modify the more activ e template represented by 52 led only to reductions in; antidiabetic activi ty. Each of the new active analogues displayed the same resistance to creat ine-like metabolism as 2. Further testing of 7, 9, and 53 in obese diabetic ob;lob mice confirmed that weight loss is induced selectively from adipose tissue, similar to the lead 1. Administration of 53 to insulin-resistant r hesus monkeys led to reductions in both fasting and post-prandial plasma gl ucose levels with concomitant reductions in plasma insulin levels, suggesti ng that the compound improved the action of endogenous insulin. Compounds 7 and 53 were selected for further preclinical development.