Velusetrag

Velusetrag
Clinical data
Other namesN-[(3-endo)-8-{(2R)-2-Hydroxy-3-[methyl(methylsulfonyl)amino]propyl}-8-azabicyclo[3.2.1]oct-3-yl]-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide
Routes of
administration		Oral
ATC code
  • None
Legal status
Legal status
Identifiers
  • N-{(1R,3r,5S)-8-[(2R)-2-Hydroxy-3-(N-methylmethanesulfonamido)propyl]-8-azabicyclo[3.2.1]octan-3-yl}-2-oxo-1-(propan-2-yl)-1,2-dihydroquinoline-3-carboxamide
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC25H36N4O5S
Molar mass504.65 g·mol−1
3D model (JSmol)
  • 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
  • InChI=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
  • Key: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]

  1. ^ "WHO Drug Information, Vol. 24, No. 1, 2010. International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names: List 63" (PDF). World Health Organization. p. 79. Retrieved 26 April 2016.
  2. ^ Vazquez-Roque M, Camilleri M (2011). "Velusetrag". Drugs of the Future. 36 (6): 447–454. doi:10.1358/dof.2011.036.06.1594078. S2CID 258477333.
  3. ^ Smith JA, Beattie DT, Marquess D, Shaw JP, Vickery RG, Humphrey PP (July 2008). "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. doi:10.1007/s00210-008-0282-y. PMID 18415081. S2CID 19726333.
  4. ^ "Theravance Biopharma: Programs". Theravance Biopharma. Retrieved 2017-05-10.
  5. ^ "Theravance and Alfa Wassermann Enter Into Agreement to Develop and Commercialize Velusetrag for Gastroparesis". www.sec.gov. Retrieved 2017-05-10.
  6. ^ Goldberg M, Li YP, Johanson JF, Mangel AW, Kitt M, Beattie DT, et al. (November 2010). "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. doi:10.1111/j.1365-2036.2010.04456.x. PMID 21039672. S2CID 8485762.
  7. ^ Manini ML, Camilleri M, Goldberg M, Sweetser S, McKinzie S, Burton D, et al. (January 2010). "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. doi:10.1111/j.1365-2982.2009.01378.x. PMC 2905526. PMID 19691492.
  8. ^ Kuo B, Barnes CN, Nguyen DD, Shaywitz D, Grimaldi M, Renzulli C, et al. (May 2021). "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. doi:10.1111/apt.16344. PMID 33811761. S2CID 233011154.
  9. ^ "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. Retrieved 2017-05-10.
  10. ^ House SA (2015-05-18). Douglas W (ed.). "Theravance's velusetrag performs well in gastroparesis study". Seeking Alpha. Retrieved 2017-05-10.
  11. ^ Morales S (2016-12-18). "FDA Gives Fast Track Designation for Gastroparesis Treatment". Diabetes Daily. Retrieved 2017-05-10.
  12. ^ "The Diabetic and Idiopathic Gastroparesis Efficacy, Safety, and Tolerability (DIGEST) Study". ClinicalTrials.gov. Retrieved 26 April 2016.