Drug discovery approaches to irritable bowel syndrome

Abstract

Challenges for new drug discovery are the unknown mechanisms underlying IBS, making it difficult to predict clinically efficacious molecular targets, limited options for translational research and disease progression biomarkers. Drugs acting locally via multiple targets (e.g., eluxadoline [The U.S. Food and Drug Administration approved Viberzi (eluxadoline) for IBS-D on May 27th 2015], crofelemer) to validated mechanisms are proving successful with tolerable safety margins. Novel mechanisms, identified and optimized based on the emerging role of nutrient signaling, probiotics or microbial products, are promising. Therapeutic treatment earlier in disease progression may improve response and have longer term benefits.

Enteric Neuronal Regulation of Intestinal Inflammation

“…The ability of the inflamed bowel to generate peristaltic reflexes along its proximodistal length is interrupted. Many small-molecule drugs have been developed over the years to modulate the output of the nervous system and, although such compounds have been employed effectively in the treatment of IBS, for example serotonergic agonists and antagonists [114], little is known about the therapeutic efficacy of neuroactive compounds in IBD.…”

G protein‐coupled estrogen receptor and estrogen receptor ligands regulate colonic motility and visceral pain

“…Based on bowel habits, IBS is classified into three subtypes: diarrhea‐predominant IBS (IBS‐D), constipation‐predominant IBS (IBS‐C), and IBS with alternating periods of diarrhea and constipation (IBS‐A) . The pathogenesis of IBS is still poorly recognized and various environmental factors, including diet, smoking, and stress participate in IBS progression . The diagnosis is presently based on the Rome IV criteria .…”

“…recognized and various environmental factors, including diet, smoking, and stress participate in IBS progression. 3 The diagnosis is presently based on the Rome IV criteria. 2 Interestingly, IBS is mainly diagnosed in women (female/male sex ratio=2:1 in survey-based and to 4:1 in practice-based diagnostics) and its incidence increases during the early adult years.…”

Serotonergic Mechanisms Regulating the GI Tract: Experimental Evidence and Therapeutic Relevance

“…Small-molecule drugs that modulate 5-HT signaling pathways have been developed for the treatment of IBS, but despite their potential, the utility of related neuroprotective agents in intestinal inflammatory diseases has not yet been trialed (Brown et al 2011; Hornby 2015). …”