velusetrag

{{Short description|Chemical compound}}

{{cs1 config|name-list-style=vanc|display-authors=6}}

{{Infobox drug

| drug_name =

| IUPAC_name = 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

| image = Velusetrag structure.svg

| width = 250

| image2 = Velusetrag2.png

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| routes_of_administration = Oral

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| legal_US = IND

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| CAS_number = 866933-46-2

| CAS_supplemental =
866933-51-9 (hydrochloride)

| ATCvet =

| ATC_prefix = None

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| PubChem = 53297466

| PubChemSubstance =

| IUPHAR_ligand = 8425

| DrugBank =

| ChemSpiderID = 28527582

| UNII = J4VNV64ARB

| KEGG = D09693

| ChEBI =

| ChEMBL = 2087337

| synonyms = N-[(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

| chemical_formula =

| C = 25 | H = 36 | N = 4 | O = 5 | S = 1

| molecular_weight =

| 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

| StdInChI_comment =

| StdInChIKey = HXLOHDZQBKCUCR-WOZUAGRISA-N

}}

Velusetrag (INN,{{cite web|title=WHO Drug Information, Vol. 24, No. 1, 2010. International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names: List 63|url=https://www.who.int/medicines/publications/druginformation/innlists/RL63.pdf|publisher=World Health Organization|access-date=26 April 2016|page=79}} 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.{{cite journal | vauthors = Vazquez-Roque M, Camilleri M |year=2011|title=Velusetrag|journal=Drugs of the Future|volume=36|issue=6|pages=447–454|doi=10.1358/dof.2011.036.06.1594078 |s2cid=258477333 }} It is a potent, selective, high efficacy 5-HT₄ receptor serotonin agonist{{cite journal | vauthors = Smith JA, Beattie DT, Marquess D, Shaw JP, Vickery RG, Humphrey PP | title = The in vitro pharmacological profile of TD-5108, a selective 5-HT(4) receptor agonist with high intrinsic activity | journal = Naunyn-Schmiedeberg's Archives of Pharmacology | volume = 378 | issue = 1 | pages = 125–137 | date = July 2008 | pmid = 18415081 | doi = 10.1007/s00210-008-0282-y | s2cid = 19726333 }} being developed by Theravance Biopharma{{Cite web|url=http://www.theravance.com/programs|title=Theravance Biopharma: Programs|website=Theravance Biopharma|access-date=2017-05-10}} and Alfa Wassermann.{{Cite web|url=https://www.sec.gov/Archives/edgar/data/1080014/000117184312003529/newsrelease.htm|title=Theravance and Alfa Wassermann Enter Into Agreement to Develop and Commercialize Velusetrag for Gastroparesis|website=www.sec.gov|access-date=2017-05-10}} 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.{{cite journal | vauthors = Goldberg M, Li YP, Johanson JF, Mangel AW, Kitt M, Beattie DT, Kersey K, Daniels O | title = 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 | journal = Alimentary Pharmacology & Therapeutics | volume = 32 | issue = 9 | pages = 1102–1112 | date = November 2010 | pmid = 21039672 | doi = 10.1111/j.1365-2036.2010.04456.x | s2cid = 8485762 }}

Velusetrag showed accelerated intestinal and colonic transit after single dosing and accelerated gastric emptying after multiple dosing in healthy volunteer subjects.{{cite journal | vauthors = Manini ML, Camilleri M, Goldberg M, Sweetser S, McKinzie S, Burton D, Wong S, Kitt MM, Li YP, Zinsmeister AR | title = Effects of Velusetrag (TD-5108) on gastrointestinal transit and bowel function in health and pharmacokinetics in health and constipation | journal = Neurogastroenterology and Motility | volume = 22 | issue = 1 | pages = 42–9, e7-8 | date = January 2010 | pmid = 19691492 | pmc = 2905526 | doi = 10.1111/j.1365-2982.2009.01378.x }} In addition, velusetrag showed accelerated gastric emptying in patients with diabetic or idiopathic gastroparesis.{{cite journal | vauthors = Kuo B, Barnes CN, Nguyen DD, Shaywitz D, Grimaldi M, Renzulli C, Canafax D, Parkman HP | title = Velusetrag accelerates gastric emptying in subjects with gastroparesis: a multicentre, double-blind, randomised, placebo-controlled, phase 2 study | journal = Alimentary Pharmacology & Therapeutics | volume = 53 | issue = 10 | pages = 1090–1097 | date = May 2021 | pmid = 33811761 | doi = 10.1111/apt.16344 | s2cid = 233011154 }} 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.{{Cite web|url=http://investor.theravance.com/releasedetail.cfm?ReleaseID=913609|title=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)|website=investor.theravance.com|access-date=2017-05-10}}{{Cite news|url=https://seekingalpha.com/news/2530306-theravances-velusetrag-performs-well-in-gastroparesis-study|title=Theravance's velusetrag performs well in gastroparesis study| vauthors = House SA | veditors = Douglas W |date=2015-05-18|work=Seeking Alpha|access-date=2017-05-10}}

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.{{Cite news|url=https://www.diabetesdaily.com/blog/fda-gives-fast-track-designation-for-gastroparesis-treatment-323878/|title=FDA Gives Fast Track Designation for Gastroparesis Treatment| vauthors = Morales S |date=2016-12-18|work=Diabetes Daily|access-date=2017-05-10}}

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.{{cite web|title=The Diabetic and Idiopathic Gastroparesis Efficacy, Safety, and Tolerability (DIGEST) Study|url=https://clinicaltrials.gov/show/NCT02267525|website=ClinicalTrials.gov|access-date=26 April 2016}}