Comparison of McN-3495 [N-(1-methyl-2-pyrrolidinylidene-N' -phenyl-1-pyrrolidinecarboximidamide], A New, Orally Effective, Hypoglycemic Agent, with the Biguanides

Abstract

McN-3495 [chemical name: N-(1-methyl-2-pyrrolidinylidene)-N'-phenyl-1-pyrrolidinecarboximidamide], a new, oral, effective hypoglycemic agent that is structurally distinct from the biguanides, has been shown to be mechanistically distinct from the biguanides and to lack comparable side effects in animals. The biguanides (phenformin, buformin, metformin), which were active when glucose was given orally to fasted rats and dogs, failed to lower fasting blood glucose or improve glucose tolerance when the glucose was administered parenterally, thus suggesting that biguanides inhibit intestinal glucose absorption. McN-3495, however, lowered the fasting concentrations of glucose and increased glucose disappearance whether the glucose was administered orally or parenterally. Furthermore, intestinal glucose transport, measured by use of the everted sac technique, was inhibited after oral pretreatment of rats with buformin and phenformin but not with McN-3495. However, both phenformin and McN-3495 inhibited glucose transport when added directly in vitro, although McN-3495 did so at higher concentrations. The reasons for the differing actions of McN-3495 and the biguanides on intestinal transport in vivo and in vitro are discussed. New models for biguanide-induced lactacidemia using normal and streptozotocin-diabetic rats were developed. In addition, a number of the gastrointestinal side effects of phenformin use were observed in animal experiments. McN-3495, at doses above projected therapeutic doses, however, did not produce lactacidemia or comparable gastrointestinal side effects. Thus, McN-3495 is a novel oral hypoglycemic agent, probably safer than phenformin, that could provide better control of blood glucose in diabetic patients.