Renzapride

Last updated
Renzapride
Renzapride.svg
Clinical data
ATC code
  • none
Identifiers
  • 4-amino-N-[(4S,5S)-1-azabicyclo[3.3.1]nonan-4-yl]-5-chloro-2-methoxybenzamide
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C16H22ClN3O2
Molar mass 323.82 g·mol−1
3D model (JSmol)
  • Clc1cc(c(OC)cc1N)C(=O)N[C@@H]3CC[N@]2C[C@@H]3CCC2
  • InChI=1S/C16H22ClN3O2/c1-22-15-8-13(18)12(17)7-11(15)16(21)19-14-4-6-20-5-2-3-10(14)9-20/h7-8,10,14H,2-6,9,18H2,1H3,(H,19,21)/t10-,14+/m0/s1 Yes check.svgY
  • Key:GZSKEXSLDPEFPT-IINYFYTJSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Renzapride is a prokinetic agent and antiemetic which acts as a full 5-HT4 agonist and partial 5-HT3 antagonist. [1] [2] It also functions as a 5-HT2B antagonist and has some affinity for the 5-HT2A and 5-HT2C receptors. [1]

Renzapride was being developed by Alizyme plc of the United Kingdom. In May 2016, EndoLogic LLC, a US-based pharmaceutical and medical device company, acquired the US and worldwide patent rights to Renzapride.

Endologic confirmed the cardiac safety of renzapride through a “Thorough QTc” study [3] and sold the rights to Atlantic Healthcare plc in 2019, [4] a specialist pharmaceutical company.

Atlantic Healthcare is focusing on the development of renzapride for the management of gastrointestinal (GI) motility in a number of rare diseases, including systemic scleroderma and cystic fibrosis, both of which are associated with chronic GI motility problems and for which there are no approved therapies.

Clinical trials

In nine diabetic patients with autonomic neuropathy, renzapride reduced the mean lag phase of gastric emptying by 20–26 min at all doses (P < 0.01) [5]

In Phase 2a studies on subjects with constipation Renzapride was shown to accelerate colonic transit (p=0.016 vs placebo P=0.009) (Ref: ATL 1251/001/CL) as well as increase daily stool frequency (p<0.005) (Ref: ATL 1251/025/CL)

Renzapride has been assessed in Phase II clinical trials with a total of 578 patients with constipation-predominant irritable bowel syndrome (IBS-C). As compared with placebo, the treatment groups reported better relief of their overall symptoms, namely abdominal pain and discomfort, increase in the number of pain free days, improved stool frequency, consistency and ease of passage of bowel movements. There were no significant differences in the reported Serious Adverse Events between treatment and placebo groups. [2] [6] [7]

In the largest of these Phase II trials, 510 subjects with IBS-C received either 1, 2 or 4 mg QD renzapride, or placebo QD for 12 weeks. The Weekly responder rate based on subject's assessment of whether they had relief from abdominal pain and/or discomfort associated with IBS during weeks 5-12 was 56% (renzapride 4 mg) vs 49% (placebo). For females the treatment effect was larger, 61% (renzapride 4 mg) vs 49% (placebo). Statistically significant effects in favour of renzapride were observed for improvements in stool consistency and increased bowel movements. [7]

In the Phase III clinical trial in IBS-C, 1798 female patients received either 2 or 4 mg Renzapride, or placebo once daily, for 12 weeks. The mean number of months with relief of overall symptoms was 0.6, 0.55 and 0.44 for renzapride 2 mg twice a day, renzapride 4 mg once a day and placebo, respectively, with both renzapride doses being statistically superior to placebo (p=0.004 and p=0.027, respectively). On responder analysis, the proportion of responders was 33.2%, 29.8%, and 24.3% for renzapride 2 mg twice a day, renzapride 4 mg once a day and placebo, respectively. [8]

The 8.9% delta between renzapride 2 mg twice daily and placebo compares favourably with other FDA approved therapies (Ford [9] ).

Related Research Articles

<span class="mw-page-title-main">Irritable bowel syndrome</span> Functional gastrointestinal disorder

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by a group of symptoms that commonly include abdominal pain, abdominal bloating and changes in the consistency of bowel movements. These symptoms may occur over a long time, sometimes for years. IBS can negatively affect quality of life and may result in missed school or work or reduced productivity at work. Disorders such as anxiety, major depression, and chronic fatigue syndrome are common among people with IBS.

<span class="mw-page-title-main">Alosetron</span> Medication

Alosetron, sold under the brand name Lotronex among others, is a 5-HT3 antagonist used for the management of severe diarrhea-predominant irritable bowel syndrome (IBS) in females only.

<span class="mw-page-title-main">Lactulose</span> Treatment for constipation and hepatic encephalopathy

Lactulose is a non-absorbable sugar used in the treatment of constipation and hepatic encephalopathy. It is administered orally for constipation, and either orally or rectally for hepatic encephalopathy. It generally begins working after 8–12 hours, but may take up to 2 days to improve constipation.

<span class="mw-page-title-main">Colestyramine</span> Pharmaceutical drug

Colestyramine (INN) or cholestyramine (USAN) is a bile acid sequestrant, which binds bile in the gastrointestinal tract to prevent its reabsorption. It is a strong ion exchange resin, which means it can exchange its chloride anions with anionic bile acids in the gastrointestinal tract and bind them strongly in the resin matrix. The functional group of the anion exchange resin is a quaternary ammonium group attached to an inert styrene-divinylbenzene copolymer.

Pouchitis is an umbrella term for inflammation of the ileal pouch, an artificial rectum surgically created out of ileum in patients who have undergone a proctocolectomy or total colectomy. The ileal pouch-anal anastomosis is created in the management of patients with ulcerative colitis, indeterminate colitis, familial adenomatous polyposis, cancer, or rarely, other colitides.

The Bristol stool scale is a diagnostic medical tool designed to classify the form of human faeces into seven categories. It is used in both clinical and experimental fields.

<span class="mw-page-title-main">Rifaximin</span> Antibiotic medication

Rifaximin, is a non-absorbable, broad spectrum antibiotic mainly used to treat travelers' diarrhea. It is based on the rifamycin antibiotics family. Since its approval in Italy in 1987, it has been licensed in over more than 30 countries for the treatment of a variety of gastrointestinal diseases like irritable bowel syndrome, and hepatic encephalopathy. It acts by inhibiting RNA synthesis in susceptible bacteria by binding to the RNA polymerase enzyme. This binding blocks translocation, which stops transcription. It is marketed under the brand name Xifaxan by Salix Pharmaceuticals.

<span class="mw-page-title-main">Tofisopam</span> Anxiolytic medication

Tofisopam is an anxiolytic that is marketed in several European countries. Chemically, it is a 2,3-benzodiazepine. Unlike other anxiolytic benzodiazepines however, tofisopam does not have anticonvulsant, sedative, skeletal muscle relaxant, motor skill-impairing or amnestic properties. While it may not be an anticonvulsant in and of itself, it has been shown to enhance the anticonvulsant action of classical 1,4-benzodiazepines and muscimol, but not sodium valproate, carbamazepine, phenobarbital, or phenytoin. Tofisopam is indicated for the treatment of anxiety and alcohol withdrawal, and is prescribed in a dosage of 50–300 mg per day divided into three doses. Peak plasma levels are attained two hours after an oral dose. Tofisopam is not reported as causing dependence to the same extent as other benzodiazepines, but is still recommended to be prescribed for a maximum of 12 weeks.

<span class="mw-page-title-main">Lubiprostone</span> Medication used for constipation

Lubiprostone, sold under the brand name Amitiza among others, is a medication used in the management of chronic idiopathic constipation, predominantly irritable bowel syndrome-associated constipation in women and opioid-induced constipation. The drug is owned by Mallinckrodt and is marketed by Takeda Pharmaceutical Company.

Donnatal is a combination medication that provides natural belladonna alkaloids in a specific fixed ratio combined with phenobarbital to provide peripheral anticholinergic/antispasmodic action and mild sedation. Donnatal is manufactured for Concordia Pharmaceuticals by IriSys, LLC. It is available as tablets and 5 mL elixir. Active ingredients are listed as: phenobarbital (16.2 mg), hyoscyamine sulfate (0.1037 mg), atropine sulfate (0.0194 mg), and scopolamine hydrobromide (0.0065 mg). The latter two ingredients are found in plants of the family Solanaceae, such as belladonna.

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

Mosapride is a gastroprokinetic agent that acts as a selective 5HT4 agonist. The major active metabolite of mosapride, known as M1, additionally acts as a 5HT3 antagonist, which accelerates gastric emptying throughout the whole of the gastrointestinal tract in humans, and is used for the treatment of gastritis, gastroesophageal reflux disease, functional dyspepsia and irritable bowel syndrome. It is recommended to be taken on an empty stomach (i.e. at least one hour before food or two hours after food).

Iberogast, also known as STW5, is a liquid formulation of nine herbs used for functional dyspepsia and irritable bowel syndrome. A proprietary blend, it was developed in Germany in 1961 and is available in other countries. Named after the genus (Iberis) of one of its ingredients, it is also claimed to possess anti-inflammatory, antioxidative and free radical-inhibiting properties as well as the ability to reduce gastric acid secretion.

Alverine is a drug used for functional gastrointestinal disorders. Alverine is a smooth muscle relaxant. Smooth muscle is a type of muscle that is not under voluntary control; it is the muscle present in places such as the gut and uterus.

<span class="mw-page-title-main">Prucalopride</span> Drug used to treat chronic constipation

Prucalopride, sold under brand names Resolor and Motegrity among others, is a medication acting as a selective, high affinity 5-HT4 receptor agonist which targets the impaired motility associated with chronic constipation, thus normalizing bowel movements. Prucalopride was approved for medical use in the European Union in 2009, in Canada in 2011, in Israel in 2014, and in the United States in December 2018. The drug has also been tested for the treatment of chronic intestinal pseudo-obstruction.

Rose Pharma is a private company that was founded in 2003 as Gastrotech Pharma and is located in Copenhagen, Denmark. The company is led by CEO Leif Helth Jensen, who is, together with Michael Forer and Florian Schönharting, also member of the Board of Directors. Rose Pharma is a clinical stage biotechnology company focused on the development of novel treatments for IBS and anorexia/cachexia associated with cancer and other major pathologies.

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

Asimadoline (EMD-61753) is an experimental drug which acts as a peripherally selective κ-opioid receptor (KOR) agonist. Because of its low penetration across the blood–brain barrier, asimadoline lacks the psychotomimetic effects of centrally acting KOR agonists, and consequently was thought to have potential for medical use. It has been studied as a possible treatment for irritable bowel syndrome, with reasonable efficacy seen in clinical trials, but it has never been approved or marketed.

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

Velusetrag (INN, 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. It is a potent, selective, high efficacy 5-HT4 receptor serotonin agonist being developed by Theravance Biopharma and Alfa Wassermann. 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.

Plecanatide, sold under the brand name Trulance, is a medication for the treatment of chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation. It is being launched in India under the brand name "Plecasoft". Plecanatide is an agonist of guanylate cyclase-C. Plecanatide increases intestinal transit and fluid through a buildup of cGMP.

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

Olorinab (APD371) is a drug being developed by Arena Pharmaceuticals for the treatment of gastrointestinal pain associated with Crohn's disease and irritable bowel syndrome. It acts as a potent and selective cannabinoid CB2 receptor agonist and is claimed to be orally active and peripherally selective. Initial Phase IIa exploratory clinical trials have been successful in patients with quiescent Crohn's disease. Arena initiated the Phase IIb Captivate trial in late July 2019 in patients with irritable bowel syndrome related pain, in constipation and diarrhea predominant sub-types. The Phase IIb trial is expected to enroll 240 participants between the ages of 18 and 70.Three doses of 10 mg, 25 mg, and 50 mg are being tested against Placebo in a 3:4 prescription ratio with a Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) masking layout.

A low-FODMAP diet is a person's global restriction of consumption of all fermentable carbohydrates (FODMAPs), recommended only for a short time. A low-FODMAP diet is recommended for managing patients with irritable bowel syndrome (IBS) and can reduce digestive symptoms of IBS including bloating and flatulence.

References

  1. 1 2 Meyers NL, Hickling RI (2008). "Pharmacology and metabolism of renzapride : a novel therapeutic agent for the potential treatment of irritable bowel syndrome". Drugs in R&D. 9 (1): 37–63. doi:10.2165/00126839-200809010-00004. PMC   7044400 . PMID   18095752.
  2. 1 2 Camilleri M, McKinzie S, Fox J, Foxx-Orenstein A, Burton D, Thomforde G, et al. (October 2004). "Effect of renzapride on transit in constipation-predominant irritable bowel syndrome". Clinical Gastroenterology and Hepatology. 2 (10): 895–904. doi:10.1016/s1542-3565(04)00391-x. PMID   15476153.
  3. ↑ "FDA accepts cardiac safety trial for gastroparesis drug". Healio. 21 May 2018. Archived from the original on 12 July 2019. Retrieved 12 July 2019.
  4. ↑ Quested T (26 June 2019). "Atlantic Healthcare pounces on big bucks US opportunity". Business Weekly. Archived from the original on 1 July 2019. Retrieved 12 July 2019.
  5. ↑ Mackie AD, Ferrington C, Cowan S, Merrick MV, Baird JD, Palmer KR (April 1991). "The effects of renzapride, a novel prokinetic agent, in diabetic gastroparesis". Alimentary Pharmacology & Therapeutics. 5 (2): 135–142. doi:10.1111/j.1365-2036.1991.tb00014.x. PMID   1888816. S2CID   20428833.
  6. ↑ Tack J, Middleton SJ, Horne MC, Piessevaux H, Bloor JS, Meyers NL, Palmer RM (June 2006). "Pilot study of the efficacy of renzapride on gastrointestinal motility and symptoms in patients with constipation-predominant irritable bowel syndrome". Alimentary Pharmacology & Therapeutics. 23 (11): 1655–1665. doi: 10.1111/j.1365-2036.2006.02940.x . PMID   16696817. S2CID   25481560.
  7. 1 2 George AM, Meyers NL, Hickling RI (May 2008). "Clinical trial: renzapride therapy for constipation-predominant irritable bowel syndrome--multicentre, randomized, placebo-controlled, double-blind study in primary healthcare setting". Alimentary Pharmacology & Therapeutics. 27 (9): 830–837. doi: 10.1111/j.1365-2036.2008.03649.x . PMID   18284648. S2CID   38167889.
  8. ↑ Lembo AJ, Cremonini F, Meyers N, Hickling R (May 2010). "Clinical trial: renzapride treatment of women with irritable bowel syndrome and constipation - a double-blind, randomized, placebo-controlled, study". Alimentary Pharmacology & Therapeutics. 31 (9): 979–990. doi: 10.1111/j.1365-2036.2010.04265.x . PMID   20163375.
  9. ↑ Ford AC (July 2010). "Renzapride in IBS: is efficacy in the eye of the beholder?". Alimentary Pharmacology & Therapeutics. 32 (1): 113–114. doi:10.1111/j.1365-2036.2010.04275.x. PMID   20597877. S2CID   28565520.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.