Ulimorelin

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,[8] and showed promising results initially in humans,[4][6] it failed in pivotal clinical trials in post operative ileus.[7]

Ulimorelin
Clinical data
ATC code
  • None
Identifiers
IUPAC name
  • (7R,10R,13S,16R)-13-cyclopropyl-7-(4-fluorobenzyl)-10,11,16-trimethyl-17-oxa-5,8,11,14-tetrazabicyclo[16.4.0]docosa-1(22),18,20-triene-6,9,12-trione
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC30H39FN4O4
Molar mass538.664 g·mol−1
3D model (JSmol)
SMILES
  • C[C@@H]1CN[C@H](C(=O)N([C@@H](C(=O)N[C@@H](C(=O)NCCCC2=CC=CC=C2O1)CC3=CC=C(C=C3)F)C)C)C4CC4
InChI
  • InChI=1S/C30H39FN4O4/c1-19-18-33-27(23-12-13-23)30(38)35(3)20(2)28(36)34-25(17-21-10-14-24(31)15-11-21)29(37)32-16-6-8-22-7-4-5-9-26(22)39-19/h4-5,7,9-11,14-15,19-20,23,25,27,33H,6,8,12-13,16-18H2,1-3H3,(H,32,37)(H,34,36)/t19-,20-,25-,27+/m1/s1
  • Key:WGYPAJVJMXQXTR-ABNZCKJZSA-N

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.[4][7]

References
  1. Hoveyda HR, Marsault E, Gagnon R, Mathieu AP, Vézina M, Landry A, et al. (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". Journal of Medicinal Chemistry. 54 (24): 8305–20. doi:10.1021/jm2007062. PMID 22106937.
  2. Fraser GL, Hoveyda HR, Tannenbaum GS (December 2008). "Pharmacological demarcation of the growth hormone, gut motility and feeding effects of ghrelin using a novel ghrelin receptor agonist". Endocrinology. 149 (12): 6280–8. doi:10.1210/en.2008-0804. PMID 18719021.
  3. Lasseter KC, Shaughnessy L, Cummings D, Pezzullo JC, Wargin W, Gagnon R, et al. (February 2008). "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. doi:10.1177/0091270007310380. PMID 18199894. S2CID 206433703.
  4. Wargin W, Thomas H, Clohs L, St-Louis C, Ejskjaer N, Gutierrez M, et al. (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". Clinical Drug Investigation. 29 (6): 409–18. doi:10.2165/00044011-200929060-00004. PMID 19432500. S2CID 23063963.
  5. Popescu I, Fleshner PR, Pezzullo JC, Charlton PA, Kosutic G, Senagore AJ (February 2010). "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. doi:10.1007/DCR.0b013e3181b54166. PMID 20087086. S2CID 25357270.
  6. Greenwood-Van Meerveld B, Kriegsman M, Nelson R (November 2011). "Ghrelin as a target for gastrointestinal motility disorders". Peptides. 32 (11): 2352–6. doi:10.1016/j.peptides.2011.03.014. PMID 21453735. S2CID 22222190.
  7. Bochicchio G, Charlton P, Pezzullo JC, 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 Journal of Surgery. 36 (1): 39–45. doi:10.1007/s00268-011-1335-9. PMC 3243849. PMID 22072430.
  8. 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". Diseases of the Colon and Rectum. 56 (7): 888–97. doi:10.1097/DCR.0b013e31829196d0. PMID 23739196. S2CID 20364202.
  9. Fraser GL, Venkova K, Hoveyda HR, Thomas H, Greenwood-Van Meerveld B (February 2009). "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. doi:10.1016/j.ejphar.2008.12.011. PMID 19121631.
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