Ulimorelin Explained

Ulimorelin (INN, USAN) (developmental code name TZP-101) is a drug with a modified cyclic peptide structure which acts as a selective agonist of the ghrelin/growth hormone secretagogue receptor (GHSR-1a).^[1] Unlike many related drugs, ulimorelin has little or no effect on growth hormone (GH) release in rats.^[2] However, like ghrelin and other ghrelin agonists, ulimorelin does stimulate GH release with concomitant increases in insulin-like growth factor 1 (IGF-1) in humans.^[3] It has been researched for enhancing gastrointestinal motility, especially in gastroparesis^[4] and in aiding recovery of bowel function following gastrointestinal surgery, where opioid analgesic drugs used for post-operative pain relief may worsen existing constipation.^{[5] [6] [7] [8]} While ulimorelin has been shown to increase both upper and lower gastrointestinal motility in rats, and showed promising results initially in humans, it failed in pivotal clinical trials in post operative ileus.

A common side effect of ghrelin is reduced blood pressure. Ulimorelin has been shown to inhibit vasoconstriction of rat arteries in vitro elicited by the α₁-adrenoceptors agonists phenylephrine and methoxamine, and to increase artery tension at high concentrations.^[9] Effects on blood pressure, however, were not observed in human clinical trials.

Notes and References

1. Hoveyda HR, Marsault E, Gagnon R, Mathieu AP, Vézina M, Landry A, Wang Z, Benakli K, Beaubien S, Saint-Louis C, Brassard M, Pinault JF, Ouellet L, Bhat S, Ramaseshan M, Peng X, Foucher L, Beauchemin S, Bhérer P, Veber DF, Peterson ML, Fraser GL . 6 . Optimization of the potency and pharmacokinetic properties of a macrocyclic ghrelin receptor agonist (Part I): Development of ulimorelin (TZP-101) from hit to clinic . Journal of Medicinal Chemistry . 54 . 24 . 8305–20 . December 2011 . 22106937 . 10.1021/jm2007062 .
2. Fraser GL, Hoveyda HR, Tannenbaum GS . Pharmacological demarcation of the growth hormone, gut motility and feeding effects of ghrelin using a novel ghrelin receptor agonist . Endocrinology . 149 . 12 . 6280–8 . December 2008 . 18719021 . 10.1210/en.2008-0804 . free .
3. Lasseter KC, Shaughnessy L, Cummings D, Pezzullo JC, Wargin W, Gagnon R, Oliva J, Kosutic G . 6 . Ghrelin agonist (TZP-101): safety, pharmacokinetics and pharmacodynamic evaluation in healthy volunteers: a phase I, first-in-human study . Journal of Clinical Pharmacology . 48 . 2 . 193–202 . February 2008 . 18199894 . 10.1177/0091270007310380 . 206433703 .
4. Wargin W, Thomas H, Clohs L, St-Louis C, Ejskjaer N, Gutierrez M, Shaughnessy L, Kosutic G . 6 . Contribution of protein binding to the pharmacokinetics of the ghrelin receptor agonist TZP-101 in healthy volunteers and adults with symptomatic gastroparesis: two randomized, double-blind studies and a binding profile study . Clinical Drug Investigation . 2009 . 29 . 6 . 409–18 . 19432500 . 10.2165/00044011-200929060-00004 . 23063963 .
5. Popescu I, Fleshner PR, Pezzullo JC, Charlton PA, Kosutic G, Senagore AJ . The Ghrelin agonist TZP-101 for management of postoperative ileus after partial colectomy: a randomized, dose-ranging, placebo-controlled clinical trial . Diseases of the Colon and Rectum . 53 . 2 . 126–34 . February 2010 . 20087086 . 10.1007/DCR.0b013e3181b54166 . 25357270 .
6. Greenwood-Van Meerveld B, Kriegsman M, Nelson R . Ghrelin as a target for gastrointestinal motility disorders . Peptides . 32 . 11 . 2352–6 . November 2011 . 21453735 . 10.1016/j.peptides.2011.03.014 . 22222190 .
7. Bochicchio G, Charlton P, Pezzullo JC, Kosutic G, Senagore A . Ghrelin agonist TZP-101/ulimorelin accelerates gastrointestinal recovery independently of opioid use and surgery type: covariate analysis of phase 2 data . World Journal of Surgery . 36 . 1 . 39–45 . January 2012 . 22072430 . 3243849 . 10.1007/s00268-011-1335-9 .
8. Shaw M, Pediconi C, McVey D, Mondou E, Quinn J, Chamblin B, Rousseau F . Safety and efficacy of ulimorelin administered postoperatively to accelerate recovery of gastrointestinal motility following partial bowel resection: results of two randomized, placebo-controlled phase 3 trials . Diseases of the Colon and Rectum . 56 . 7 . 888–97 . July 2013 . 23739196 . 10.1097/DCR.0b013e31829196d0 . 20364202 .
9. Fraser GL, Venkova K, Hoveyda HR, Thomas H, Greenwood-Van Meerveld B . Effect of the ghrelin receptor agonist TZP-101 on colonic transit in a rat model of postoperative ileus . European Journal of Pharmacology . 604 . 1–3 . 132–7 . February 2009 . 19121631 . 10.1016/j.ejphar.2008.12.011 .