CSTI-300 (SMP-100); a novel 5-HT3 receptor partial agonist with potential to treat patients with irritable bowel syndrome or carcinoid syndrome

Alexander Roberts, Gillian Grafton, Andrew D. Powell, Kristian Brock, Chunlin Chen, Dejian Xie, Jinkun Huang, Shuang Liu, Alison J. Cooper, Catherine A. Brady, Omar Qureshi, Zania Stamataki, David D. Manning, Nicholas A. Moore, Bruce J. Sargent, Peter R. Guzzo, Nicholas M. Barnes

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3 Citations (Scopus)
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Abstract

The 5-hydroxytryptamine (5-HT) (serotonin) 5-HT3 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-HT3 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-HT3 receptor (Ki 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 Ki value for the 5-HT3 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 t1/2 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-HT3 receptor antagonists, such as alosetron.
Original languageEnglish
Pages (from-to)122-134
Number of pages13
JournalJournal of Pharmacology and Experimental Therapeutics
Volume373
Issue number1
Early online date16 Mar 2020
DOIs
Publication statusPublished - 1 Apr 2020

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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