TY - JOUR T1 - Pharmacologic Comparison of Clinical Neutral Endopeptidase Inhibitors in a Rat Model of Acute Secretory Diarrhea JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.115.231167 SP - jpet.115.231167 AU - David W Griggs AU - Michael J Prinsen AU - Jonathan Oliva AU - Mary A Campbell AU - Stacy D Arnett AU - Deena Tajfirouz AU - Peter G Ruminski AU - Ying Yu AU - Brian Bond AU - Yuhua Ji AU - Georg Neckermann AU - Robert K Choy AU - Eugenio de Hostos AU - Marvin J Meyers Y1 - 2016/01/01 UR - http://jpet.aspetjournals.org/content/early/2016/02/23/jpet.115.231167.abstract N2 - Racecadotril (acetorphan) is a neutral endopeptidase (NEP) inhibitor with known anti-diarrheal activity in animals and humans. However, it suffers from shortcomings in humans that might be improved upon with newer drugs in this class that have progressed to the clinic for non-enteric disease indications. To identify potentially superior NEP inhibitors with immediate clinical utility for diarrhea treatment, we compared their efficacy and pharmacologic properties in a rat intestinal hypersecretion model. Racecadotril and seven other clinical-stage inhibitors of NEP were obtained or synthesized. Enzyme potency and specificity were compared using purified peptidases. Compounds were orally administered to rats before administration of castor oil to induce diarrhea. Stool weight was recorded over four hours. To assess other pharmacologic properties, select compounds were orally administered to normal or castor oil-treated rats, blood and tissue samples collected at multiple time points, and active compound concentrations determined by mass spectroscopy. NEP enzyme activity was measured in tissue homogenates. Three previously untested clinical NEP inhibitors delayed diarrhea onset and reduced total stool output, with little or no effect on intestinal motility assessed by the charcoal meal test. Each was shown to be a potent, highly specific inhibitor of NEP. Each exhibited greater suppression of NEP activity in intestinal and non-intestinal tissues than racecadotril, and sustained this inhibition longer. These results suggest newer clinical-stage NEP inhibitors originally developed for other indications may be directly repositioned for treatment of acute secretory diarrhea and offer advantages over racecadotril, such as less frequent dosing and potentially improved efficacy. ER -