Vaillancourt V A, Larsen S D, Tanis S P, Burr J E, Connell M A, Cudahy M M, Evans B R, Fisher P V, May P D, Meglasson M D, Robinson D D, Stevens F C, Tucker J A, Vidmar T J, Yu J H
Departments of Medicinal Chemistry, Pharmacology, and Research Biostatistics, Pharmacia Corporation, 301 Henrietta Street, Kalamazoo, Michigan 49007, USA.
J Med Chem. 2001 Apr 12;44(8):1231-48. doi: 10.1021/jm000094n.
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.
3-胍基丙酸（1）已被证明在非胰岛素依赖型糖尿病（NIDDM）动物模型中既能提高胰岛素敏感性，又能选择性地促进脂肪组织减重。然而，1也已被证明是肌酸转运体和肌酸激酶的底物，导致其作为相应的N-磷酸盐在肌肉组织中显著蓄积。最近发现相应的氨基胍类似物2保留了1的抗糖尿病活性，同时对类似肌酸的代谢明显不敏感，这表明它在肌肉中蓄积的可能性较小。对2进行了进一步的结构修饰，以研究在保持对类似肌酸代谢的抗性的同时，抗糖尿病效力是否可以增强。诸如α-烷基化、同系化和氨基胍的生物电子等排体取代等修饰均对抗糖尿病活性不利。然而，发现简单的区域异构体氨基胍基乙酸9和二氨基胍基乙酸类似物7与2等效，最终导致发现活性明显更高的二氨基胍基乙酸区域异构体52和53。对以52为代表的更具活性的模板进行进一步修饰只会导致抗糖尿病活性降低。每种新的活性类似物对类似肌酸的代谢表现出与2相同的抗性。在肥胖糖尿病ob/ob小鼠中对7、9和53进行的进一步测试证实，与先导化合物1类似，体重减轻是由脂肪组织选择性诱导的。给胰岛素抵抗的恒河猴施用53导致空腹和餐后血浆葡萄糖水平降低，同时血浆胰岛素水平降低，这表明该化合物改善了内源性胰岛素的作用。选择化合物7和53进行进一步的临床前开发。
