Velusetrag Explained

Iupac Name:N--2-oxo-1-(propan-2-yl)-1,2-dihydroquinoline-3-carboxamide
Width:250
Routes Of Administration:Oral
Legal Us:IND
Cas Number:866933-46-2
Cas Supplemental:
866933-51-9 (hydrochloride)
Atc Prefix:None
Pubchem:53297466
Iuphar Ligand:8425
Chemspiderid:28527582
Unii:J4VNV64ARB
Kegg:D09693
Chembl:2087337
Synonyms:N-[(3-''endo'')-8-{(2''R'')-2-Hydroxy-3-[methyl(methylsulfonyl)amino]propyl}-8-azabicyclo[3.2.1]oct-3-yl]-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide
C:25
H:36
N:4
O:5
S:1
Smiles:CC(C)N1C2=CC=CC=C2C=C(C1=O)C(=O)N[C@H]3C[C@H]4CC[C@@H](C3)N4C[C@H](CN(C)S(=O)(=O)C)O
Stdinchi:1S/C25H36N4O5S/c1-16(2)29-23-8-6-5-7-17(23)11-22(25(29)32)24(31)26-18-12-19-9-10-20(13-18)28(19)15-21(30)14-27(3)35(4,33)34/h5-8,11,16,18-21,30H,9-10,12-15H2,1-4H3,(H,26,31)/t18-,19+,20-,21-/m0/s1
Stdinchikey:HXLOHDZQBKCUCR-WOZUAGRISA-N

Velusetrag (INN,[1] USAN; previously known as TD-5108) is an experimental drug candidate for the treatment of gastric neuromuscular disorders including gastroparesis, and lower gastrointestinal motility disorders including chronic idiopathic constipation and irritable bowel syndrome.[2] It is a potent, selective, high efficacy 5-HT4 receptor serotonin agonist[3] being developed by Theravance Biopharma[4] and Alfa Wassermann.[5] Velusetrag demonstrates less selectivity for other serotonin receptors, such as 5-HT2 and 5-HT3, to earlier generation 5-HT agonists like cisapride and tegaserod.

In a large clinical trial in patients with chronic idiopathic constipation (n=401), velusetrag statistically and clinically improved the frequency and consistency of complete spontaneous bowel movements (CSBMs) compared to placebo. Doses of 15 and 30 mg were well tolerated compared to placebo.[6]

Velusetrag showed accelerated intestinal and colonic transit after single dosing and accelerated gastric emptying after multiple dosing in healthy volunteer subjects.[7] In addition, velusetrag showed accelerated gastric emptying in patients with diabetic or idiopathic gastroparesis.[8] The proportion of patients who experienced at least a 20% improvement is gastric emptying ranged from 20% to 52% for velusetrag dosed patients and 5% for placebo patients.[9] [10]

On December 6, 2016, Theravance Biopharma announced that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation to velusetrag for the treatment of symptoms associated with diabetic and idiopathic Gastroparesis.[11]

As of May 10, 2017, Velusetrag is being studied, at doses of 5, 15 and 30 mg over a 12-week treatment period, for symptomatic improvement in patients with diabetic or idiopathic gastroparesis in the DIGEST study.[12]

See also

Notes and References

  1. Web site: WHO Drug Information, Vol. 24, No. 1, 2010. International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names: List 63. World Health Organization. 26 April 2016. 79.
  2. Vazquez-Roque M, Camilleri M . 2011. Velusetrag. Drugs of the Future. 36. 6. 447–454. 10.1358/dof.2011.036.06.1594078 . 258477333 .
  3. Smith JA, Beattie DT, Marquess D, Shaw JP, Vickery RG, Humphrey PP . The in vitro pharmacological profile of TD-5108, a selective 5-HT(4) receptor agonist with high intrinsic activity . Naunyn-Schmiedeberg's Archives of Pharmacology . 378 . 1 . 125–137 . July 2008 . 18415081 . 10.1007/s00210-008-0282-y . 19726333 .
  4. Web site: Theravance Biopharma: Programs. Theravance Biopharma. 2017-05-10.
  5. Web site: Theravance and Alfa Wassermann Enter Into Agreement to Develop and Commercialize Velusetrag for Gastroparesis. www.sec.gov. 2017-05-10.
  6. Goldberg M, Li YP, Johanson JF, Mangel AW, Kitt M, Beattie DT, Kersey K, Daniels O . Clinical trial: the efficacy and tolerability of velusetrag, a selective 5-HT4 agonist with high intrinsic activity, in chronic idiopathic constipation - a 4-week, randomized, double-blind, placebo-controlled, dose-response study . Alimentary Pharmacology & Therapeutics . 32 . 9 . 1102–1112 . November 2010 . 21039672 . 10.1111/j.1365-2036.2010.04456.x . 8485762 .
  7. Manini ML, Camilleri M, Goldberg M, Sweetser S, McKinzie S, Burton D, Wong S, Kitt MM, Li YP, Zinsmeister AR . Effects of Velusetrag (TD-5108) on gastrointestinal transit and bowel function in health and pharmacokinetics in health and constipation . Neurogastroenterology and Motility . 22 . 1 . 42–9, e7-8 . January 2010 . 19691492 . 2905526 . 10.1111/j.1365-2982.2009.01378.x .
  8. Kuo B, Barnes CN, Nguyen DD, Shaywitz D, Grimaldi M, Renzulli C, Canafax D, Parkman HP . Velusetrag accelerates gastric emptying in subjects with gastroparesis: a multicentre, double-blind, randomised, placebo-controlled, phase 2 study . Alimentary Pharmacology & Therapeutics . 53 . 10 . 1090–1097 . May 2021 . 33811761 . 10.1111/apt.16344 . 233011154 .
  9. Web site: Theravance Biopharma Presents Positive Phase 2 Study Data on Velusetrag (TD-5108) for Treatment of Gastroparesis in "Poster of Distinction" at Digestive Disease Week (DDW) 2015 (NASDAQ:TBPH). investor.theravance.com. 2017-05-10.
  10. News: Theravance's velusetrag performs well in gastroparesis study. House SA . Douglas W . 2015-05-18. Seeking Alpha. 2017-05-10.
  11. News: FDA Gives Fast Track Designation for Gastroparesis Treatment. Morales S . 2016-12-18. Diabetes Daily. 2017-05-10.
  12. Web site: The Diabetic and Idiopathic Gastroparesis Efficacy, Safety, and Tolerability (DIGEST) Study. ClinicalTrials.gov. 26 April 2016.

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