Design, SAR and pharmacology of GM-611, the first acid-stable nonpeptide motilin receptor agonist

Based on the acid-decomposition mechanism of EMA, the acid-stable EMA derivative GM-611 was designed and selected as a candidate for further development and clinical trials. In binding studies, GM-611 as well as porcine motilin (pMTL) displaced 125I-pMTL bound to homogenates of rabbit and monkey duodenal smooth muscle tissues, with similar displacement curves. In in vitro experiments, GM-611 induced concentration-dependent contractions in isolated longitudinal segments of rabbit duodenum. The contractile responses due to GM-611 were competitively inhibited by pretreatment with a selective motilin antagonist, GM-109, but not by pretreatment with atropine, tetrodotoxin, naloxone, hexamethonium or tropisetron. GM-611 was stable to acid and showed little antibacterial activity. GM-611 had potent motilin agonist activity and gastric emptying effects in normal animals as well as in delayed gastric emptying animal models in monkeys and dogs when given i.v. or p.o. GM-611 is in phase IIb clinical trials for the treatment of gastroparesis. Applications in other gastrointestinal disorders are also being studied.