CSTI-300 (SMP-100); a Novel 5-HT3 Receptor Partial Agonist with Potential to Treat Patients with Irritable Bowel Syndrome or Carcinoid Syndrome
A Roberts, Gillian Grafton, Andrew D. Powell, Kristian Brock, Chun‐Lin Chen, Dejian Xie, Jinkun Huang, Shuang Liu, Alison Cooper, Catherine Brady, Omar Qureshi, Zania Stamataki, David D. Manning, Nicholas Moore, Bruce J. Sargent, Peter R. Guzzo, Nicholas M. Barnes
Abstract
The 5-hydroxytryptamine (5-HT) (serotonin) 5-HT 3 receptor represents a clinical target for antagonists to deliver symptomatic relief to patients with diarrhea-predominant irritable bowel syndrome (IBS-d) or carcinoid syndrome. Unfortunately, this pharmacological strategy can present side effects (e.g., severe constipation). The present study investigates the potential of a novel 5-HT 3 receptor partial agonist, CSTI-300, to treat patients with IBS-d and other conditions associated with discomfort from colonic distension, with a predicted reduced side-effect profile. The in vitro and in vivo preclinical pharmacology of the drug CSTI-300 was investigated to explore the potential to treat patients with IBS-d. CSTI-300 displayed selective high affinity for the human and rat 5-HT 3 receptor (K i approximately 2.0 nM) and acted as a partial agonist (approximately 30%–50% intrinsic efficacy) in vitro. In an in vivo model of IBS-d, the rat colon distension model, CSTI-300 displayed dose-dependent efficacy. In addition, oral administration of CSTI-300 to dogs that achieved plasma levels of the drug exceeding the K i value for the 5-HT 3 receptor failed to either evoke emesis or alter the state of feces. Pharmacokinetics for CSTI-300 in rat and dog identified high levels of oral availability with t 1/2 range of 1.6–4.4 hours. The preclinical pharmacology of the lead candidate drug, CSTI-300, supports the potential of this novel drug to offer symptomatic relief to patients with irritable bowel syndrome and carcinoid syndrome with a rationale for a reduced "on-target" side-effect profile relative to 5-HT 3 receptor antagonists, such as alosetron. SIGNIFICANCE STATEMENT There is a lack of effective current treatment for diarrhea-predominant irritable bowel syndrome and carcinoid syndrome, and in both conditions, overactivity of the 5-hydroxytryptamine (5-HT) 5-HT 3 receptor is thought to be implicated in the pathophysiology. Because 5-HT 3 receptor blockade with antagonists results in significant side effects, we present evidence that treatment with a suitable 5-HT 3 receptor partial agonist will alleviate some symptoms associated with these conditions yet, without fully inhibiting the receptor, predict a less pronounced side-effect profile associated with this therapeutic strategy.