Ulimorelin

Ulimorelin
Clinical data
ATC code
  • None
Identifiers
CAS Number
PubChem CID
ChemSpider
KEGG
Chemical and physical data
Formula C30H39FN4O4
Molar mass 538.653 g/mol
3D model (JSmol)

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,[9] and showed promising results initially in humans,[10][11] it failed in pivotal clinical trials in post operative ileus.[12]

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.[13] Effects on blood pressure, however, were not observed in human clinical trials.[4][7]

References

  1. ↑ Hoveyda, H.R.; Marsault, E.; Gagnon, R.; Mathieu, A.P.; Vézina, M.; Landry, A.; Wang, Z.; Benakli, K.; Beaubien, S. (22 December 2011). "Optimization of the potency and pharmacokinetic properties of a macrocyclic ghrelin receptor agonist (Part I): Development of ulimorelin (TZP-101) from hit to clinic". J Med Chem. 54: 8305–20. PMID 22106937.
  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. 2008 Dec;149(12):6280-8. doi: 10.1210/en.2008-0804 PMID 18719021
  3. ↑ Gutierrez, M.; Shaughnessy, L.; Cummings, D.R.; Pezzullo, J.; Reeve, R.; Reilly, R.; Kosutic, G (2007). "Ghrelin Agonist (TZP-101): Safety, Pharmacokinetics and Pharmacodynamics: A Multi-dose Evaluation in Healthy Volunteers". AMS. 24.
  4. 1 2 Wargin W, Thomas H, Clohs L, St-Louis C, Ejskjaer N, Gutierrez M, Shaughnessy L, Kosutic G. 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. Clin Drug Investig. 2009;29(6):409-18. doi: 10.2165/00044011-200929060-00004 PMID 19432500
  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. Dis Colon Rectum. 2010 Feb;53(2):126-34. doi: 10.1007/DCR.0b013e3181b54166 PMID 20087086
  6. ↑ Greenwood-Van Meerveld B, Kriegsman M, Nelson R. Ghrelin as a target for gastrointestinal motility disorders. Peptides. 2011 Nov;32(11):2352-6. doi: 10.1016/j.peptides.2011.03.014 PMID 21453735
  7. 1 2 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 J Surg. 2012 Jan;36(1):39-45. doi: 10.1007/s00268-011-1335-9 PMID 22072430
  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. Dis Colon Rectum. 2013 Jul;56(7):888-97. doi: 10.1097/DCR.0b013e31829196d0 PMID 23739196
  9. ↑ Shaw, M.; Pediconi, C.; McVey, D.; Mondou, E.; Quinn, J.; Chamblin, B.; Rousseau, F. (July 2013). "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". Dis Colon Rectum. 56 (7): 888–897. PMID 23739196.
  10. ↑ Wargin, W.; Thomas, H.; Clohs, L.; St-Louis, C; Ejskajaer, N.; Gutierrez, M.; Shaughnessy, L.; Kosutic, G. (2009). "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". Clin Drug Investig. 29 (6): 409–18. PMID 19432500.
  11. ↑ Greenwood-Van Meerveld, B.; Kriegsman, M.; Nelson, R. (November 2011). "Ghrelin as a target for gastrointestinal motility disorders". Peptides. 32 (11): 2352–6. PMID 21453735.
  12. ↑ Bochicchio, G.; Charlton, P.; Pezzullo, J.C.; Kosutic, G.; Senagore, A. (January 2012). "Ghrelin agonist TZP-101/ulimorelin accelerates gastrointestinal recovery independently of opioid use and surgery type: covariate analysis of phase 2 data". World J Surg. 36 (1): 39–45.
  13. ↑ Fraser, GL; Venkova, K.; Hoveyda, HR; Thomas, H.; Greenwood-Van Meerveld, B. (2009). "Effect of the ghrelin receptor agonist TZP-101 on colonic transit in a rat model of postoperative ileus". Eur J Pharmacol. 604: 132–137.
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