TY - JOUR
T1 - CSTI-300 (SMP-100); a novel 5-HT3 receptor partial agonist with potential to treat patients with irritable bowel syndrome or carcinoid syndrome
AU - Roberts, Alexander
AU - Grafton, Gillian
AU - Powell, Andrew D.
AU - Brock, Kristian
AU - Chen, Chunlin
AU - Xie, Dejian
AU - Huang, Jinkun
AU - Liu, Shuang
AU - Cooper, Alison J.
AU - Brady, Catherine A.
AU - Qureshi, Omar
AU - Stamataki, Zania
AU - Manning, David D.
AU - Moore, Nicholas A.
AU - Sargent, Bruce J.
AU - Guzzo, Peter R.
AU - Barnes, Nicholas M.
PY - 2020/4/1
Y1 - 2020/4/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85082093389&partnerID=8YFLogxK
UR - http://jpet.aspetjournals.org/content/suppl/2020/02/26/jpet.119.261008.DC1
U2 - 10.1124/jpet.119.261008
DO - 10.1124/jpet.119.261008
M3 - Article
SN - 0022-3565
VL - 373
SP - 122
EP - 134
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 1
ER -