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The Pharmacology of TD-8954, a Potent and Selective 5-HT(4) Receptor Agonist with Gastrointestinal Prokinetic Properties.

Beattie DT, Armstrong SR, Vickery RG, Tsuruda PR, Campbell CB, Richardson C, McCullough JL, Daniels O, Kersey K, Li YP, Kim KH - Front Pharmacol (2011)

Bottom Line: In a single ascending oral dose study in healthy human subjects, TD-8954 (0.1-20 mg) increased bowel movement frequency and reduced the time to first stool.It is concluded that TD-8954 is a potent and selective 5-HT(4) receptor agonist in vitro, with robust in vivo stimulatory activity in the gastrointestinal (GI) tract of guinea pigs, rats, dogs, and humans.TD-8954 may have clinical utility in patients with disorders of reduced GI motility.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Theravance, Inc. South San Francisco, CA, USA.

ABSTRACT
This study evaluated the in vitro and in vivo pharmacological properties of TD-8954, a potent and selective 5-HT(4) receptor agonist. TD-8954 had high affinity (pK(i) = 9.4) for human recombinant 5-HT(4(c)) (h5-HT(4(c))) receptors, and selectivity (>2,000-fold) over all other 5-hydroxytryptamine (5-HT) receptors and non-5-HT receptors, ion channels, enzymes and transporters tested (n = 78). TD-8954 produced an elevation of cAMP in HEK-293 cells expressing the h5-HT(4(c)) receptor (pEC(50) = 9.3), and contracted the guinea pig colonic longitudinal muscle/myenteric plexus preparation (pEC(50) = 8.6). TD-8954 had moderate intrinsic activity in the in vitro assays. In conscious guinea pigs, subcutaneous administration of TD-8954 (0.03-3 mg/kg) increased the colonic transit of carmine red dye, reducing the time taken for its excretion. Following intraduodenal dosing to anesthetized rats, TD-8954 (0.03-10 mg/kg) evoked a dose-dependent relaxation of the esophagus. Following oral administration to conscious dogs, TD-8954 (10 and 30 μg/kg) produced an increase in contractility of the antrum, duodenum, and jejunum. In a single ascending oral dose study in healthy human subjects, TD-8954 (0.1-20 mg) increased bowel movement frequency and reduced the time to first stool. It is concluded that TD-8954 is a potent and selective 5-HT(4) receptor agonist in vitro, with robust in vivo stimulatory activity in the gastrointestinal (GI) tract of guinea pigs, rats, dogs, and humans. TD-8954 may have clinical utility in patients with disorders of reduced GI motility.

No MeSH data available.


(A) The mean number of bowel movements, and (B) the cumulative percentage of subjects responding with a bowel movement within 24 h following the oral dosing of TD-8954 (0.1–20 mg) and placebo to healthy human subjects (n = 5–14 per group). Each dose of TD-8954 produced a statistically significant effect compared to placebo (*p < 0.03, Wilcoxon rank sum test vs. placebo).
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Figure 7: (A) The mean number of bowel movements, and (B) the cumulative percentage of subjects responding with a bowel movement within 24 h following the oral dosing of TD-8954 (0.1–20 mg) and placebo to healthy human subjects (n = 5–14 per group). Each dose of TD-8954 produced a statistically significant effect compared to placebo (*p < 0.03, Wilcoxon rank sum test vs. placebo).

Mentions: In healthy human subjects, GI prokinetic effects of TD-8954 (0.1–20 mg) were observed (Figure 7). The number of bowel movements from 0 to 24 h after each TD-8954 dose was increased significantly relative to placebo (p < 0.03 upon comparison of each TD-8954 treated group and placebo, based on Wilcoxon rank sum test). Compared to placebo, each TD-8954 dose was associated with a statistically significant reduction in the time to first bowel movement (p < 0.05 for all treatment groups comparing difference in survival function between each TD-8954 treated group and placebo obtained by log-rank test).


The Pharmacology of TD-8954, a Potent and Selective 5-HT(4) Receptor Agonist with Gastrointestinal Prokinetic Properties.

Beattie DT, Armstrong SR, Vickery RG, Tsuruda PR, Campbell CB, Richardson C, McCullough JL, Daniels O, Kersey K, Li YP, Kim KH - Front Pharmacol (2011)

(A) The mean number of bowel movements, and (B) the cumulative percentage of subjects responding with a bowel movement within 24 h following the oral dosing of TD-8954 (0.1–20 mg) and placebo to healthy human subjects (n = 5–14 per group). Each dose of TD-8954 produced a statistically significant effect compared to placebo (*p < 0.03, Wilcoxon rank sum test vs. placebo).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3108484&req=5

Figure 7: (A) The mean number of bowel movements, and (B) the cumulative percentage of subjects responding with a bowel movement within 24 h following the oral dosing of TD-8954 (0.1–20 mg) and placebo to healthy human subjects (n = 5–14 per group). Each dose of TD-8954 produced a statistically significant effect compared to placebo (*p < 0.03, Wilcoxon rank sum test vs. placebo).
Mentions: In healthy human subjects, GI prokinetic effects of TD-8954 (0.1–20 mg) were observed (Figure 7). The number of bowel movements from 0 to 24 h after each TD-8954 dose was increased significantly relative to placebo (p < 0.03 upon comparison of each TD-8954 treated group and placebo, based on Wilcoxon rank sum test). Compared to placebo, each TD-8954 dose was associated with a statistically significant reduction in the time to first bowel movement (p < 0.05 for all treatment groups comparing difference in survival function between each TD-8954 treated group and placebo obtained by log-rank test).

Bottom Line: In a single ascending oral dose study in healthy human subjects, TD-8954 (0.1-20 mg) increased bowel movement frequency and reduced the time to first stool.It is concluded that TD-8954 is a potent and selective 5-HT(4) receptor agonist in vitro, with robust in vivo stimulatory activity in the gastrointestinal (GI) tract of guinea pigs, rats, dogs, and humans.TD-8954 may have clinical utility in patients with disorders of reduced GI motility.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Theravance, Inc. South San Francisco, CA, USA.

ABSTRACT
This study evaluated the in vitro and in vivo pharmacological properties of TD-8954, a potent and selective 5-HT(4) receptor agonist. TD-8954 had high affinity (pK(i) = 9.4) for human recombinant 5-HT(4(c)) (h5-HT(4(c))) receptors, and selectivity (>2,000-fold) over all other 5-hydroxytryptamine (5-HT) receptors and non-5-HT receptors, ion channels, enzymes and transporters tested (n = 78). TD-8954 produced an elevation of cAMP in HEK-293 cells expressing the h5-HT(4(c)) receptor (pEC(50) = 9.3), and contracted the guinea pig colonic longitudinal muscle/myenteric plexus preparation (pEC(50) = 8.6). TD-8954 had moderate intrinsic activity in the in vitro assays. In conscious guinea pigs, subcutaneous administration of TD-8954 (0.03-3 mg/kg) increased the colonic transit of carmine red dye, reducing the time taken for its excretion. Following intraduodenal dosing to anesthetized rats, TD-8954 (0.03-10 mg/kg) evoked a dose-dependent relaxation of the esophagus. Following oral administration to conscious dogs, TD-8954 (10 and 30 μg/kg) produced an increase in contractility of the antrum, duodenum, and jejunum. In a single ascending oral dose study in healthy human subjects, TD-8954 (0.1-20 mg) increased bowel movement frequency and reduced the time to first stool. It is concluded that TD-8954 is a potent and selective 5-HT(4) receptor agonist in vitro, with robust in vivo stimulatory activity in the gastrointestinal (GI) tract of guinea pigs, rats, dogs, and humans. TD-8954 may have clinical utility in patients with disorders of reduced GI motility.

No MeSH data available.