Ulimorelin

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Ulimorelin
Ulimorelin structure.png
Clinical data
ATC code
  • None
Identifiers
  • (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
Formula C30H39FN4O4
Molar mass 538.664 g·mol−1
3D model (JSmol)
  • 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=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

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]

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]

Related Research Articles

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<span class="mw-page-title-main">GHRP-6</span> Chemical compound

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<span class="mw-page-title-main">Tabimorelin</span> Chemical compound

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<span class="mw-page-title-main">Cinitapride</span> Chemical compound

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A prokinetic agent is a type of small peptide drug which enhances gastrointestinal motility by increasing the frequency or strength of contractions, but without disrupting their rhythm. They are used to treat certain gastrointestinal symptoms, including abdominal discomfort, bloating, constipation, heart burn, nausea, and vomiting; and certain gastrointestinal disorders, including irritable bowel syndrome, gastritis, gastroparesis, and functional dyspepsia.

<span class="mw-page-title-main">Velusetrag</span> Chemical compound

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<span class="mw-page-title-main">Pralmorelin</span> Chemical compound

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<span class="mw-page-title-main">Anamorelin</span> Chemical compound

Anamorelin (INN), also known as anamorelin hydrochloride, is a non-peptide, orally-active, centrally-penetrant, selective agonist of the ghrelin/growth hormone secretagogue receptor (GHSR) with appetite-enhancing and anabolic effects which is under development by Helsinn Healthcare SA for the treatment of cancer cachexia and anorexia.

<span class="mw-page-title-main">Relamorelin</span> Chemical compound

Relamorelin is a synthetic peptide, centrally penetrant, selective agonist of the ghrelin/growth hormone secretagogue receptor (GHSR) which is under development by Allergan pharmaceuticals for the treatment of diabetic gastroparesis, chronic idiopathic constipation, and anorexia nervosa. It is a pentapeptide and an analogue of ghrelin with improved potency and pharmacokinetics. In humans, relamorelin produces increases in plasma growth hormone, prolactin, and cortisol levels, and, like other GHSR agonists, increases appetite. As of June 2015, relamorelin is in phase II clinical trials for diabetic gastroparesis and constipation. The United States Food and Drug Administration (FDA) has granted Fast Track designation to relamorelin for diabetic gastroparesis. The development of the drug is uncertain as the most recent mention of it was in a 2019 SEC filing from the drug manufacturer lists the drug's expected launch year as 2024, but not in subsequent filings or press releases.

<span class="mw-page-title-main">Ipamorelin</span> Peptide selective agonist of the ghrelin/growth hormone secretagogue receptor

Ipamorelin (INN) (developmental code name NNC 26-0161) is a peptide selective agonist of the ghrelin/growth hormone secretagogue receptor (GHS) and a growth hormone secretagogue. It is a pentapeptide with the amino acid sequence Aib-His-D-2-Nal-D-Phe-Lys-NH2 that was derived from GHRP-1.

<span class="mw-page-title-main">Examorelin</span> Chemical compound

Examorelin (INN) (developmental code names EP-23905, MF-6003), also known as hexarelin, is a potent, synthetic, peptidic, orally-active, centrally-penetrant, and highly selective agonist of the ghrelin/growth hormone secretagogue receptor (GHSR) and a growth hormone secretagogue which was developed by Mediolanum Farmaceutici. It is a hexapeptide with the amino acid sequence His-D-2-methyl-Trp-Ala-Trp-D-Phe-Lys-NH2 which was derived from GHRP-6. These GH-releasing peptides have no sequence similarity to ghrelin, but mimic ghrelin by acting as agonists at the ghrelin receptor.

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. 1 2 3 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. 1 2 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. 1 2 3 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. 1 2 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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