AMRI has discovered 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 intrinsic activity (Figure 1).
Figure 1. Functional activities of 5-HT3 receptor partial agonists falling within the Target Area are predicted to provide an IBS medicine with an improved action and safety profile.
AMRI has identified its first preclinical candidate, ALB-137391(a) and back-up candidates that are available for partnering.
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Partial activation of both GPCRs and ion channels is an increasingly popular drug discovery strategy which principally has been used to improve side effect profiles identified in first generation compounds. Some examples of marketed drugs which have benefited from this approach include ABILIFY® (D2 partial agonist) and CHANTIX® (a4ß2 nAChR partial agonist). Partial agonists are unique in that they can elicit a “dual action” at the target receptor. They have capacity to partially activate a receptor but also can dampen the action of a naturally-occurring or endogenous full agonist. As a result a partial agonist can provide an intermediate biological response as compared to antagonists (which fully turn off a biological response) or natural agonist (which activate or drive a biological response). Much like a dimmer switch, AMRI compounds exhibit these characteristic buffering responses at the 5-HT3 receptor (Figure 2).
Figure 2: Confocal fluorescence microscopy in HEK-293 cells expressing h5-HT3A shows an AMRI compound exhibiting partial agonism in contrast to alosetron (antagonist) and 5-HT (serotonin, full agonist). Green indicates 5-HT3 receptor activity.
AMRI believes that modulating 5-HT3 receptor function, but not obliterating it, via a partial agonist approach may alleviate the symptoms of IBS without producing severe effects on gastrointestinal function such as severe constipation or ischemic colitis associated with certain potent 5-HT3 receptor antagonists.
IBS 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 or constipation, 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.
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 function of the 5-HT3 receptor 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 GlaxoSmithKline 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, as 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 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 safety. AMRI’s approach to target compounds that partially activate the 5-HT3 receptor represents a significant mechanistic departure from the 5-HT3 receptor antagonist class of activity. AMRI believes compounds which modulate 5-HT3 receptor function can lead to superior treatments of IBS and in particular may expand the treatment potential of this class of agents to include multiple subtypes of IBS.