Methods of using macrocyclic agonists of the ghrelin receptor for treatment of gastrointestinal motility disorders
View Patent ↗The present invention provides novel conformationally-defined macrocyclic compounds that have been demonstrated to be selective agonists of the ghrelin receptor (growth hormone secretagogue receptor, GHS-R1a and subtypes, isoforms and variants thereof). Such compounds are useful as medicaments for treatment and prevention of a range of medical conditions characterized by disturbed gastrointestinal motility including, but not limited to, post-surgical gastroparesis and post-operative ileus in combination with opioid-induced bowel dysfunction. These agents are effective for multiple disorders at dose levels equivalent to those required to treat a single disorder.
1. A method of stimulating gastrointestinal motility comprising administering to a subject suffering from at least two disorders caused by gastrointestinal dysmotility an effective amount of a compound having any of the following structures:
or a pharmaceutically acceptable salt thereof.
2. The method of claim 1 , wherein the compound is administered orally.
3. The method of claim 1 , wherein the compound is administered parenterally.
4. The method of claim 1 , wherein the compound is administered intracranially.
5. The method of claim 1 , wherein the subject is a mammal.
6. The method of claim 3 , wherein the subject is a human.
7. The method of claim 1 , wherein the compound is co-administered with an additional agent useful for stimulating gastrointestinal motility.
8. The method of claim 1 , wherein the disorders caused by gastrointestinal dysmotility are selected from the group consisting of postoperative ileus, gastroparesis, idiopathic gastroparesis, diabetic gastroparesis and post-surgical gastroparesis, opioid-induced bowel dysfunction, chronic intestinal pseudo-obstruction, short bowel syndrome, emesis, constipation-predominant irritable bowel syndrome (IBS), delayed gastric emptying, gastroesophageal reflux disease (GERD), gastric ulcers, and Crohn's disease.
9. The method of claim 1 , wherein one of the disorders is postoperative ileus.
10. The method of claim 1 , wherein one of the disorders is diabetic gastroparesis or post-surgical gastroparesis.
11. The method of claim 1 , wherein the disorders are postoperative ileus and opioid-induced bowel dysfunction.
12. The method of claim 1 , wherein the disorders are post-surgical gastroparesis and opioid-induced bowel dysfunction.
13. The method of claim 1 , wherein at least two disorders occur concurrently.
14. The method of claim 1 , wherein at least two disorders occur sequentially.
15. The method of claim 1 , wherein a dose level of the compound having the structure shown in claim 3 to treat the at least two disorders is an equivalent dose level to that required to treat a single disorder caused by gastrointestinal dysmotility.
16. The method of claim 1 , wherein the dose level of the compound having the structure shown in claim 3 is in a range of about 50-150% of a dose level required to treat a single disorder caused by gastrointestinal dysmotility.