Corticotropin-Releasing Factor Receptor Antagonists
Corticotropin-releasing factor (CRF) is a peptide that functions as a neurotransmitter in the brain. It plays a critical role in coordinating the body’s overall response to stress, and it interacts with two known receptor subtypes, CRF1 and CRF2. Two companies that are investigating CRF receptor antagonists for irritable bowel syndrome are Research Corp Technologies, which has a compound in preclinical development, and Neurocrine Biosciences, which has an agent in Phase I clinical trials. The latter agent is discussed in detail here.
Mechanism Of Action
Preclinical models have demonstrated that selective CRF1 receptor antagonists can block stress responses. Consequently, this mechanism may be a good target for drugs to improve the symptoms of such conditions as anxiety, depression, and functional gastrointestinal disease.
Neurocrine Biosciences is developing NBI-34041 for the potential treatment of irritable bowel syndrome, anxiety, and depression. The compound is in Phase I clinical trials for all three indications. NBI-34041 is the lead in a series of compounds targeting the CRF1 receptor. Preclinical models have demonstrated that selective CRF1 receptor antagonists can block stress responses. Neurocrine was originally developing the agent in collaboration with GSK, but the compound is no longer included in the latter’s pipeline.
According to preliminary results from a Phase I dose-escalation study, the agent demonstrates rapid absorption and good dose proportionality, and its plasma half-life supports a once-daily dosing schedule.
Investigation into novel approaches to combat altered gastrointestinal motility in irritable bowel syndrome is relatively limited; the majority of R&D programs are heavily focused on relieving irritable bowel syndrome-associated pain. The following paragraphs discuss one compound, a chloride-channel activator, under investigation for the potential relief of constipation.
Mechanism Of Action
Activation of chloride channels in gastrointestinal epithelial cells increases intestinal water secretion, potentially boosting gut motility and relieving constipation.
Sucampo Pharmaceuticals is developing SPI-0211, a chloride-channel activator, for the potential treatment of constipation and irritable bowel syndrome in the United States. In April 2003, Sucampo announced that it had launched a Phase II clinical trial in the United States to evaluate SPI-0211 ‘s safety and efficacy in 200C-irritable bowel syndrome patients.
SPI-0211 is a bicyclic fatty acid that activates CIC-2 chloride channels located on the gut epithelium, increasing intestinal water. The results of a multicenter, randomized, placebo-controlled study involving 242 patients with constipation were presented at the 2003 Digestive Disease Week meeting. The researchers administered 24 µg of SPI-0211 twice daily for four weeks.
Patients who received SPI-0211 experienced a significant increase in the frequency of spontaneous bowel movements; within 24 hours of treatment, 57% of these patients experienced spontaneous bowel movements compared with 37% of the placebo group. The SPI-0211-treated patients also experienced improvements in stool consistency and straining. Adverse events, including headache, nausea, and diarrhea, were more commonly reported in the drug-treated group, but, overall, SPI-0211 was safe and well tolerated.
In January 2004, Sucampo announced the completion of a second Phase III clinical study of SPI-0211. The study involved 237 constipated patients in 20 centers across the United States. According to the company, the results duplicated the significant results of the first efficacy study.