Pharmacologic Comparison of Clinical Neutral Endopeptidase Inhibitors in a Rat Model of Acute Secretory Diarrhea

Abstract

Racecadotril (acetorphan) is a neutral endopeptidase (NEP) inhibitor with known antidiarrheal activity in animals and humans; however, in humans, it suffers from shortcomings that might be improved with newer drugs in this class that have progressed to the clinic for nonenteric 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 4 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 nonintestinal tissues than did racecadotril and sustained this inhibition longer. These results suggest that 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.

The Active Ingredients Identification and Antidiarrheal Mechanism Analysis of Plantago asiatica L. Superfine Powder

“…Thirty minutes later, the mice were euthanized, and the small intestine was immediately isolated. The travel distance of the charcoal meal and the total length of the intestine were measured 5 times, and the toner propulsion rate was expressed as the percentage of the distance traveled by the charcoal meal relative to the total length of the small intestine ( Griggs et al, 2016 ).…”

Insight Into the Binding Mode Knowledge of New Possible Anti-Hypertensive Compounds Designed in Silico Using Neutral Endopeptidase (NEP) As A Target.

“…One of these enzymes is the Neutral Endopeptidase, also called Neprilysin (NEP) [5][6][7] . This protein is responsible for the degradation of natriuretic peptides, degradation of kinins, and adrenomedullin 8,9 . The natriuretic peptides can be seen as endogenous inhibitors of the renin-angiotensin system (RAS) 10 .…”

A comprehensive review of therapeutic approaches available for the treatment of cholera

“…This effectiveness is limited because the fluid delivery itself does not provide symptom relief, nor does it eliminate V. cholerae infection and nor does it interfere with the action mechanism of its toxin. [26][27] Another concern hindering this type of treatment is that often the water used in developing countries is contaminated, which can be an unresolved problem when it is necessary to replenish a large amount of water. Standard treatments for cholera and other secretory diarrhoea also include drugs that decrease intestinal motility.…”

“…This effectiveness is limited because the fluid delivery itself does not provide symptom relief, nor does it eliminate V. cholerae infection and nor does it interfere with the action mechanism of its toxin. [ 26–27 ]…”