title: 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.
authors.affiliation: Center for World Health and Medicine, Saint Louis University, St. Louis, Missouri (D.W.G, M.J.P, J.O., M.A.C., S.D.A., D.T., P.G.R., M.J.M); Gateway Pharmacology Laboratories, St. Louis, Missouri (Y.Y, B.B); and PATH, San Francisco, California (Y.J., G.N., R.K.M.C, E.dH.) dgriggs4@slu.edu.
authors.forename: David W
authors.initials: DW
authors.lastname: Griggs
authors.affiliation: Center for World Health and Medicine, Saint Louis University, St. Louis, Missouri (D.W.G, M.J.P, J.O., M.A.C., S.D.A., D.T., P.G.R., M.J.M); Gateway Pharmacology Laboratories, St. Louis, Missouri (Y.Y, B.B); and PATH, San Francisco, California (Y.J., G.N., R.K.M.C, E.dH.).
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Prinsen
authors.affiliation: Center for World Health and Medicine, Saint Louis University, St. Louis, Missouri (D.W.G, M.J.P, J.O., M.A.C., S.D.A., D.T., P.G.R., M.J.M); Gateway Pharmacology Laboratories, St. Louis, Missouri (Y.Y, B.B); and PATH, San Francisco, California (Y.J., G.N., R.K.M.C, E.dH.).
authors.forename: Jonathan
authors.initials: J
authors.lastname: Oliva
authors.affiliation: Center for World Health and Medicine, Saint Louis University, St. Louis, Missouri (D.W.G, M.J.P, J.O., M.A.C., S.D.A., D.T., P.G.R., M.J.M); Gateway Pharmacology Laboratories, St. Louis, Missouri (Y.Y, B.B); and PATH, San Francisco, California (Y.J., G.N., R.K.M.C, E.dH.).
authors.forename: Mary A
authors.initials: MA
authors.lastname: Campbell
authors.affiliation: Center for World Health and Medicine, Saint Louis University, St. Louis, Missouri (D.W.G, M.J.P, J.O., M.A.C., S.D.A., D.T., P.G.R., M.J.M); Gateway Pharmacology Laboratories, St. Louis, Missouri (Y.Y, B.B); and PATH, San Francisco, California (Y.J., G.N., R.K.M.C, E.dH.).
authors.forename: Stacy D
authors.initials: SD
authors.lastname: Arnett
authors.affiliation: Center for World Health and Medicine, Saint Louis University, St. Louis, Missouri (D.W.G, M.J.P, J.O., M.A.C., S.D.A., D.T., P.G.R., M.J.M); Gateway Pharmacology Laboratories, St. Louis, Missouri (Y.Y, B.B); and PATH, San Francisco, California (Y.J., G.N., R.K.M.C, E.dH.).
authors.forename: Deena
authors.initials: D
authors.lastname: Tajfirouz
authors.affiliation: Center for World Health and Medicine, Saint Louis University, St. Louis, Missouri (D.W.G, M.J.P, J.O., M.A.C., S.D.A., D.T., P.G.R., M.J.M); Gateway Pharmacology Laboratories, St. Louis, Missouri (Y.Y, B.B); and PATH, San Francisco, California (Y.J., G.N., R.K.M.C, E.dH.).
authors.forename: Peter G
authors.initials: PG
authors.lastname: Ruminski
authors.affiliation: Center for World Health and Medicine, Saint Louis University, St. Louis, Missouri (D.W.G, M.J.P, J.O., M.A.C., S.D.A., D.T., P.G.R., M.J.M); Gateway Pharmacology Laboratories, St. Louis, Missouri (Y.Y, B.B); and PATH, San Francisco, California (Y.J., G.N., R.K.M.C, E.dH.).
authors.forename: Ying
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Center for World Health and Medicine, Saint Louis University, St. Louis, Missouri (D.W.G, M.J.P, J.O., M.A.C., S.D.A., D.T., P.G.R., M.J.M); Gateway Pharmacology Laboratories, St. Louis, Missouri (Y.Y, B.B); and PATH, San Francisco, California (Y.J., G.N., R.K.M.C, E.dH.).
authors.forename: Brian R
authors.initials: BR
authors.lastname: Bond
authors.affiliation: Center for World Health and Medicine, Saint Louis University, St. Louis, Missouri (D.W.G, M.J.P, J.O., M.A.C., S.D.A., D.T., P.G.R., M.J.M); Gateway Pharmacology Laboratories, St. Louis, Missouri (Y.Y, B.B); and PATH, San Francisco, California (Y.J., G.N., R.K.M.C, E.dH.).
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Ji
authors.affiliation: Center for World Health and Medicine, Saint Louis University, St. Louis, Missouri (D.W.G, M.J.P, J.O., M.A.C., S.D.A., D.T., P.G.R., M.J.M); Gateway Pharmacology Laboratories, St. Louis, Missouri (Y.Y, B.B); and PATH, San Francisco, California (Y.J., G.N., R.K.M.C, E.dH.).
authors.forename: Georg
authors.initials: G
authors.lastname: Neckermann
authors.affiliation: Center for World Health and Medicine, Saint Louis University, St. Louis, Missouri (D.W.G, M.J.P, J.O., M.A.C., S.D.A., D.T., P.G.R., M.J.M); Gateway Pharmacology Laboratories, St. Louis, Missouri (Y.Y, B.B); and PATH, San Francisco, California (Y.J., G.N., R.K.M.C, E.dH.).
authors.forename: Robert K M
authors.initials: RK
authors.lastname: Choy
authors.affiliation: Center for World Health and Medicine, Saint Louis University, St. Louis, Missouri (D.W.G, M.J.P, J.O., M.A.C., S.D.A., D.T., P.G.R., M.J.M); Gateway Pharmacology Laboratories, St. Louis, Missouri (Y.Y, B.B); and PATH, San Francisco, California (Y.J., G.N., R.K.M.C, E.dH.).
authors.forename: Eugenio
authors.initials: E
authors.lastname: de Hostos
authors.affiliation: Center for World Health and Medicine, Saint Louis University, St. Louis, Missouri (D.W.G, M.J.P, J.O., M.A.C., S.D.A., D.T., P.G.R., M.J.M); Gateway Pharmacology Laboratories, St. Louis, Missouri (Y.Y, B.B); and PATH, San Francisco, California (Y.J., G.N., R.K.M.C, E.dH.).
authors.forename: Marvin J
authors.initials: MJ
authors.lastname: Meyers
mesh_terms: D000818:Animals; D000930:Antidiarrheals / Q000627:therapeutic use*; D002368:Castor Oil; D002606:Charcoal / Q000494:pharmacology; D003967:Diarrhea / Q000139:chemically induced / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D010450:Endopeptidases / Q000378:metabolism*; D005243:Feces; D005769:Gastrointestinal Motility / Q000187:drug effects; D008297:Male; D011480:Protease Inhibitors / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D015244:Thiorphan / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D000930:Antidiarrheals; D011480:Protease Inhibitors; D002606:Charcoal; C049331:racecadotril; D002368:Castor Oil; D015244:Thiorphan; D010450:Endopeptidases