Preclinical gastrointestinal prokinetic efficacy and endocrine effects of the ghrelin mimetic RM-131.

Abstract

AIMS:

The 28 amino acid hormone ghrelin, the natural ligand for the growth hormone secretagogue, or ghrelin receptor (GHR), has diverse physiological functions, including a possible role as a gastrointestinal prokinetic. The synthetic ghrelin mimetic RM-131 is in Phase II clinical trials for treatment of diabetic gastroparesis and other gastrointestinal (GI) disorders. We aimed to determine the relative potency of RM-131, when compared to other GI ghrelin mimetics, to predict efficacy and determine the role of RM-131 in models of inflammatory bowel disease.

MAIN METHODS:

We evaluated and compared ghrelin, RM-131 and other synthetic ghrelin mimetics for their prokinetic potency in models of gastrointestinal disorders in the rat and we evaluated the endocrine (rats and dogs) and anti-inflammatory effects (mice) of the ghrelin mimetic RM-131.

KEY FINDINGS:

The pentapeptide RM-131 increased gastric emptying in rodent models of ileus. RM-131 is about 100-fold more potent than human ghrelin and is 600 to 1800-fold more potent, when compared to several investigational ghrelin mimetics tested in clinical trials. RM-131 has anti-inflammatory effects and significantly increases survival and reduces macroscopic markers of tissue damage in a TNBS model of inflammatory bowel disease. RM-131 treatment shows a transient increase in growth hormone levels in Beagle dogs and rats, returning to baseline upon chronic treatment. Significant effects on glucose and insulin are not observed in chronic studies.

SIGNIFICANCE:

RM-131's potency, efficacy and endocrine profile, are promising attributes for the treatment of diverse functional gastrointestinal disorders in humans.

• Authors: Lex Van der Ploeg, Haley Laken, Shubh Sharma, Rakesh Datta, Heather Halem, Jesse Dong, Caroline Touvay, Marc Teillot, Patrick Noonan, Lou Tartaglia, Liz Stoner, Bart Henderson, Keith Gottesdiener, Michael Culler
• Journal: Life sciences (Life Sci) Vol. 109 Issue 1 Pg. 20-9 (Jul 25 2014) ISSN: 1879-0631 [Electronic] Netherlands
• PMID: 24931905 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Anti-Inflammatory Agents
• Gastrointestinal Agents
• Ghrelin
• Growth Hormone

Topics

• Animals
• Anti-Inflammatory Agents (chemistry, therapeutic use)
• Diabetes Complications (drug therapy)
• Dogs
• Gastric Emptying (drug effects)
• Gastrointestinal Agents (chemistry, therapeutic use)
• Gastrointestinal Diseases (drug therapy)
• Gastrointestinal Motility (drug effects)
• Gastroparesis (drug therapy)
• Ghrelin (chemistry, therapeutic use)
• Growth Hormone (metabolism)
• Humans
• Ileus (drug therapy)
• Inflammatory Bowel Diseases (drug therapy)
• Male
• Mice
• Rats
• Rats, Sprague-Dawley