Constipation is an important health burden that reduces the quality of life for countless millions of people. Symptom-centric
therapeutics are often used to treat
constipation due to unknown etiology, but in many cases, these drugs are either inadequate or have significant side effects. More recently, synthetic
peptide agonists for epithelial
guanylyl cyclase C (GC-C) have been developed which are effective at treating
constipation in a sub-population of adult
constipation patients. The first to market was
linaclotide that is structurally related to the diarrheagenic
enterotoxin, but this was followed by
plecanatide, which more closely resembles endogenous
uroguanylin. Both the drugs exhibit almost identical clinical efficacy in about 20% of patients, with
diarrhea being a common side effect. Despite the potential for reduced side effects with
plecanatide, detailed analysis suggests that clinically, they are very similar. Ongoing clinical and preclinical studies with these drugs suggest that treating
constipation might be the tip of the iceberg in terms of clinical utility. The expression of cGMP signaling components could be diagnostic for functional bowel disorders, and increasing cGMP using GC-C agonists or
phosphodiesterase inhibitors has huge potential for treating enteric
pain,
ulcerative colitis, and for the
chemoprevention of
colorectal cancer.