Irritable Bowel Syndrome (IBS) – Program Summary

AMRI’s IBS program is in the late discovery stage. AMRI has identified a chemical series which members exhibit a range of functional activity at the 5-HT₃ receptor. Compounds vary from those that fully block 5-HT₃ receptor function (silent antagonists) to those which moderate receptor function (partial agonists). The range of functional activity identified is broad and therefore, in principle, multiple compounds may be identified to treat a range of IBS symptoms (diarrhea, constipation or mixed IBS symptoms). The program’s objective is to target 5-HT₃ receptor partial agonists which have low to moderate efficacy profiles (See Figure 1).

Figure 1:

Figure 1. AMRI is targeting compounds that are low to moderate 5-HT₃ receptor partial agonists. Functional activities of 5-HT₃ receptor ligands which fall between alosetron and DDP733 (a relatively high efficacy 5-HT₃ receptor partial agonist) are predicted to provide an IBS medicine with an improved action and safety profile.

Leading 5-HT₃ receptor partial agonists are presently being evaluated for identification of a candidate to initiate pre-clinical safety studies. Leading compounds have excellent in vivo activity in animal models, including an extended duration of pharmacological action over competitor compounds. Additionally, in vitro studies predict the leading compounds to have a low probability of drug/drug interactions and low risk for cardiovascular side effects. Collectively, these properties are expected to yield a superior development candidate.

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IBS: The Disease

IBS-D is a painful, debilitating functional disorder of the bowel that affects the quality of life for millions of men and women each day. The typical sufferer can experience frequent diarrhea, severe abdominal cramps, and altered bowel habits. IBS disease management in the U.S. costs $8 billion annually in direct medical care costs and as high as $25 billion in indirect economic costs. As these figures indicate, IBS is one of the major gastrointestinal diseases, yet few treatments are available for IBS sufferers.

Although the underlying cause of IBS is unknown, common symptoms of pain and altered bowel habits point to a dysfunction of neural pathways involved with sensory or motor information. Therefore, researchers have focused on understanding the biological receptors that control these pathways.

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Understanding the Relationship between 5-HT₃ Receptors and Serotonin

Serotonin, a key neurotransmitter synthesized and stored in the GI tract, plays a major role in the normal function of the gut. Serotonin binding to 5-HT receptors activates pathways of the enteric nervous system and central nervous system which can ultimately translate into gut movement or the perception of pain. One type of 5-HT receptor, the 5-HT₃ receptor, is located on certain nerve endings within the intestinal wall. The 5-HT₃ receptor’s function is to propagate sensory information. There is good evidence that compounds which modulate serotonin action at the 5-HT₃ receptor will lead to improvements in the treatment of IBS.

In fact, of the few medications developed to treat IBS, the most successful exploit the 5-HT₃ receptor. Lotronex^® (alosetron hydrochloride), a 5-HT₃ receptor blocker, was introduced by Glaxo in 2000. Although this compound controlled diarrhea and pain for many IBS patients the medication was quickly withdrawn from the market because it appeared to be associated with rare cases of ischemic colitis, a potentially serious condition. Remarkably, the FDA later reinstated the drug, a first in the agency’s history, because the patient demand was so great. This is a testimony to the effectiveness of alosetron for many patients and highlights the unmet medical need associated with IBS. Alosetron hydrochloride tablets are now available under restricted conditions to women in whom the medical benefits outweigh the risks.

In contrast to alosetron’s record, a number of 5-HT₃ receptor blockers have been in commercial use for years, being safe effective agents for the treatment of chemotherapy induced nausea and vomiting with no reports of ischemic colitis. One of these anti-emetic compounds, ramosetron, was repurposed for potential application in IBS therapy. In October 2008, Irribow^® (ramosetron hydrochloride) was approved in Japan for the treatment of IBS-D. No ischemic colitis events have been reported from ramosetron use in clinical trials.

Together, these findings argue that new 5-HT₃ receptor modulators can be identified with improved properties. AMRI believes compounds which moderate 5-HT₃ receptor function may lead to superior treatments of IBS and in particular may expand the treatment potential of this class of agents to include all types of IBS.

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