The novel, potent and highly selective 5‐HT<sub>4</sub>receptor agonist YH12852 significantly improves both upper and lower gastrointestinal motility

Jeong, Eun Jeong; Chung, Soo Yong; 韩红,; Oh, Sewoong; Sim, Jae Young

doi:10.1111/bph.14096

Cited by 11 publications

(12 citation statements)

References 52 publications

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“…Other high‐affinity agonists have also been developed including naronapride (ATI‐7505), velusetrag (TD‐5108), and YH12852. YH12852 and naronapride have high affinity for human 5‐HT 4(a) and 5‐HT 4(b) isoforms, respectively, and velusetrag (TD‐5108) is highly potent at the 5‐HT 4(c) receptor splice variant . While these drugs are still in development, like prucalopride, they appear to be clinically effective in patients with chronic constipation, with no apparent side effects and they target 5‐HT 4 R isoforms expressed in the human intestine (Table ).…”

Section: ‐Ht4rs and Prokinetic Agentsmentioning

confidence: 99%

Luminal 5‐HT₄ receptors—A successful target for prokinetic actions

Gwynne

Bornstein

2019

Neurogastroenterology Motil

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The prokinetic effects of 5‐HT4 receptor (5‐HT4R) agonists have been utilized clinically for almost three decades to relieve symptoms of constipation. Surprisingly, the mechanism(s) of action of these compounds is still being debated. Recent studies highlight luminal 5‐HT4Rs as an alternative and effective target for these prokinetic agents. These include the study by Shokrollahi et al (2019, Neurogastroenterol Motil, e13598) published in the current issue of Neurogastroenterology and Motility, who found that activation of mucosal 5‐HT4Rs by intraluminal prucalopride, significantly enhanced propulsive motor patterns in rabbit colon. The authors highlight the idea that development of agonists targeting luminal 5‐HT4Rs in the colonic mucosa might be more effective and safer in achieving prokinetic effects on intestinal motility. The purpose of this mini‐review is to discuss the evidence for luminal 5‐HT4Rs as an emerging target for prokinetic agents in facilitating propulsive motor patterns in the colon.

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Section: ‐Ht4rs and Prokinetic Agentsmentioning

confidence: 99%

Luminal 5‐HT₄ receptors—A successful target for prokinetic actions

Gwynne

Bornstein

2019

Neurogastroenterology Motil

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“…However, no phase 3 trials of velusetrag for constipation are currently registered on ClinicalTrials.gov. Another highly selective 5-HT(4) receptor agonist, YH12852, accelerated upper and lower intestinal transit in animal models 81 . Human studies are awaited.…”

Section: Development Of Novel Therapeutic Agents For the Treatment Ofmentioning

confidence: 99%

Recent advances in understanding and managing chronic constipation

Prichard

Bharucha

2018

F1000Res

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Constipation, a condition characterized by heterogeneous symptoms, is common in Western society. It is associated with reduced physical health, mental health, and social functioning. Because constipation is rarely due to a life-threatening disease (for example, colon cancer), current guidelines recommend empiric therapy. Limited surveys suggest that fewer than half of treated individuals are satisfied with treatment, perhaps because the efficacy of drugs is limited, they are associated with undesirable side effects, or they may not target the underlying pathophysiology. For example, although a substantial proportion of constipated patients have a defecatory disorder that is more appropriately treated with pelvic floor biofeedback therapy than with laxatives, virtually no pharmacological trials formally assessed for anorectal dysfunction. Recent advances in investigational tools have improved our understanding of the physiology and pathophysiology of colonic and defecatory functions. In particular, colonic and anorectal high-resolution manometry are now available. High-resolution anorectal manometry, which is increasingly used in clinical practice, at least in the United States, provides a refined assessment of anorectal pressures and may uncover structural abnormalities. Advances in our understanding of colonic molecular physiology have led to the development of new therapeutic agents (such as secretagogues, pro-kinetics, inhibitors of bile acid transporters and ion exchangers). However, because clinical trials compare these newer agents with placebo, their efficacy relative to traditional laxatives is unknown. This article reviews these physiologic, diagnostic, and therapeutic advances and focuses particularly on newer therapeutic agents.

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“…[20] YH12852 was also approximately three times more potent than prucalopride for contractile activity in the distal colon of guinea pigs (mean half maximal effective concentration: 4.2 vs. 13 nM). [20], [21] Furthermore, all electrocardiogram outputs were qualitatively and quantitatively normal in cynomolgus monkeys, which received a single oral dose of YH12852 up to at 60 mg/kg/day. YH12852 exhibited high selectivity for the human 5-HT 4 receptors while YH12852 had no significant affinity for other 5-HT (5-HT 1A , 5-HT 1B , 5-HT 2A , 5-HT 2B or 5-HT 3 ) and non 5-HT receptors or channels.…”

Section: Accepted Articlementioning

confidence: 91%

YH12852, a Potent and Selective Receptor Agonist of 5‐hydroxytryptamine, Increased Gastrointestinal Motility in Healthy Volunteers and Patients With Functional Constipation

Lee

Moon

Yoo

et al. 2020

Clinical Translational Sci

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Gastrointestinal (GI) motility disorders are common, decreases quality of life, and imposes a substantial economic burden. YH12852 is a novel agonist of 5‐hydroxytryptamine for the treatment of GI motility disorders. This phase I/IIa study assessed the tolerability, pharmacodynamic (PD) and pharmacokinetic (PK) profiles of YH12852. In the multiple dose (MD) cohort, healthy subjects and patients with functional constipation were randomized and received orally YH12852 at 0.3, 0.5, 1, 2, or 3 mg or prucalopride 2 mg or their matching placebo, once daily for 14 days after breakfast. In the multiple low‐dose cohort (MLD), healthy subjects randomly received once‐daily oral doses of YH12852 at 0.05 or 0.1 mg for 14 days after breakfast. Questionnaires, gastric emptying breath test for PDs, and plasma samples for PKs were collected. In the MD cohort, a total of 56 subjects (29 healthy volunteers and 27 patients with functional constipation) were randomized, of whom 48 completed the study. In the MLD cohort, a total of 16 healthy subjects were randomized, and 15 subjects completed the study. YH12852 increased the average weekly frequency of spontaneous bowel movements and loosened the stool. In addition, YH12852 increased quality of life satisfaction, and decreased severity of constipation symptom and GI symptoms. YH12852 was safe and well‐tolerated up to 3 mg and showed nearly dose proportional PKs. In conclusion, YH12852 was safe and enhanced GI motility. YH12852 can be developed as an effective treatment option for GI motility disorders, including functional constipation. Further studies are warranted to confirm this possibility.

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The novel, potent and highly selective 5‐HT₄receptor agonist YH12852 significantly improves both upper and lower gastrointestinal motility

Cited by 11 publications

References 52 publications

Luminal 5‐HT₄ receptors—A successful target for prokinetic actions

Luminal 5‐HT₄ receptors—A successful target for prokinetic actions

Recent advances in understanding and managing chronic constipation

YH12852, a Potent and Selective Receptor Agonist of 5‐hydroxytryptamine, Increased Gastrointestinal Motility in Healthy Volunteers and Patients With Functional Constipation

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The novel, potent and highly selective 5‐HT4receptor agonist YH12852 significantly improves both upper and lower gastrointestinal motility

Cited by 11 publications

References 52 publications

Luminal 5‐HT4 receptors—A successful target for prokinetic actions

Luminal 5‐HT4 receptors—A successful target for prokinetic actions

Recent advances in understanding and managing chronic constipation

YH12852, a Potent and Selective Receptor Agonist of 5‐hydroxytryptamine, Increased Gastrointestinal Motility in Healthy Volunteers and Patients With Functional Constipation

Contact Info

Product

Resources

About

The novel, potent and highly selective 5‐HT₄receptor agonist YH12852 significantly improves both upper and lower gastrointestinal motility

Luminal 5‐HT₄ receptors—A successful target for prokinetic actions

Luminal 5‐HT₄ receptors—A successful target for prokinetic actions