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5-HT Receptor Modulators


Overview

Clinical research has shown that modulation of 5-HT3 and 5-HT4 receptors affects visceral pain sensation and intestinal transit. The serotonin (5-HT) receptor modulator drug class has received the majority of irritable bowel syndrome researchers’ attention for nearly a decade. However, early agents in this class — alosetron (GlaxoSmithKline’s Lotronex) and tegaserod (Novartis’s Zelnorm/Zelmac) — have encountered considerable opposition during the approval process as a result of safety concerns revealed during clinical trials and postmarketing studies. These agents have been approved in the United States, but their prescription (particularly prescription of alosetron) is tightly regulated. In addition, because 5-HT receptor modulators have specificity for a single motility symptom (either diarrhea or constipation), more than 50% of the irritable bowel syndrome population is necessarily excluded from treatment with any given 5-HT modulator.

The challenge for emerging agents within this class is to demonstrate significant improvements in both efficacy and safety over existing agents to gain wider approval. Several companies are pursuing 5-HT receptor modulators for the treatment of irritable bowel syndrome. GlaxoSmithKline (GSK), Mitsubishi-Tokyo Pharma, Pharmagene, and Meiji Seika Kaisha have discovery-phase programs, while Solvay, Alizyme, and Eisai have agents in later-stage development.

Mechanism Of Action

Agents in the 5-HT receptor modulator class stimulate or inhibit the activity of 5-HT receptors in the gut, reducing visceral pain sensations and altering intestinal transit in irritable bowel syndrome patients.

TABLE : Emerging Therapies in Development for Irritable Bowel Syndrome

Compound Development Phase Marketing Company
5-HT receptor modulators
Cilansetron
United States D Solvay
Europe III Solvay
Japan
Renzapride
United States II Alizyme
Europe II Alizyme
Japan
E-3620
United States
Europe
Japan II Eisai
Tachykinin receptor antagonists
Nepadutant
United States
Europe II Menarini
Japan
Saredutant
United States
Europe II Sanofi-Synthelabo
Japan
Talnetant
United States
Europe II GlaxoSmithKline
Japan
Cholecystokinin A receptor antagonists
Dexloxiglumide
United States D Forest Laboratories/RottaPharm
Europe III RottaPharm
Japan
Opioid receptor modulators
PTI-901
United States D Pain Therapeutics
Europe
Japan
Asimadoline
United States
Europe II Merck KGaA
Japan
Corticotrophin-releasing factor receptor antagonists
NBI-34041
United States
Europe I Neurocrine Biosciences
Japan
Chloride-channel activators
SPI-0211 (RU-0211)
United States II Sucampo Pharmaceuticals
Europe
Japan

D = Discontinued.

Cilansetron

Renzapride

E-3620

Eisai is developing E-3620, an agent in Phase II clinical trials in Japan for irritable bowel syndrome, gastric motility disorders, and gastritis. Like renzapride, E-3620 is a dual 5-HT3 antagonist/5-HT4 agonist. In 1999, the company reported that treatment with E-3620 is associated with an improvement in the symptoms of diarrhea and the sense of fullness and anorexia associated with chronic gastritis and irritable bowel syndrome.

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