Beloranib

Last updated
Beloranib
Beloranib.svg
Names
Preferred IUPAC name
(3R,4S,5S,6R)-5-Methoxy-4-[(2R,3R)-2-methyl-3-(3-methylbut-2-en-1-yl)oxiran-2-yl]-1-oxaspiro[2.5]octan-6-yl (2E)-3-{4-[2-(dimethylamino)ethoxy]phenyl}prop-2-enoate
Other names
CKD-732; ZGN-433
Identifiers
3D model (JSmol)
ChemSpider
PubChem CID
UNII
  • InChI=1S/C29H41NO6/c1-20(2)7-13-24-28(3,36-24)27-26(32-6)23(15-16-29(27)19-34-29)35-25(31)14-10-21-8-11-22(12-9-21)33-18-17-30(4)5/h7-12,14,23-24,26-27H,13,15-19H2,1-6H3/b14-10+/t23-,24-,26-,27-,28+,29+/m1/s1 X mark.svgN
    Key: ZEZFKUBILQRZCK-MJSCXXSSSA-N X mark.svgN
  • InChI=1/C29H41NO6/c1-20(2)7-13-24-28(3,36-24)27-26(32-6)23(15-16-29(27)19-34-29)35-25(31)14-10-21-8-11-22(12-9-21)33-18-17-30(4)5/h7-12,14,23-24,26-27H,13,15-19H2,1-6H3/b14-10+/t23-,24-,26-,27-,28+,29+/m1/s1
    Key: ZEZFKUBILQRZCK-MJSCXXSSBU
  • O=C(O[C@H]2[C@@H](OC)[C@@H]([C@]1(OC1)CC2)[C@]3(O[C@@H]3C\C=C(/C)C)C)\C=C\c4ccc(OCCN(C)C)cc4
Properties
C29H41NO6
Molar mass 499.648 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Beloranib is a former drug candidate for the treatment of obesity. It was discovered by CKD Pharmaceuticals and its clinical development was led by Zafgen. [1] Drug development was halted in 2016 after deaths during clinical trials. [2]

Contents

Mechanism of action

Beloranib, an analog of the natural chemical compound fumagillin, is an inhibitor of the enzyme METAP2. [3] It was originally designed as angiogenesis inhibitor for the treatment of cancer. [4] However, once the potential anti-obesity effects of METAP2 inhibition became apparent, the clinical development began to focus on these effects and beloranib has shown positive results in preliminary clinical trials for this indication. [5]

Clinical trials

A Phase I trial was published in 2013, [6] finding a dose that led to weight loss in obese women in comparison to placebo. Results from a Phase II clinical trial for obesity were promising with clinically meaningful weight loss and improvements in cardiometabolic risk factors in the treated group. [7] Zafgen continued with a Phase III trial for Prader–Willi syndrome. [8]

In December 2015, Zafgen halted the Phase III clinical trial of beloranib for Prader–Willi syndrome after a second patient death in order to determine whether the deaths were treatment-related. [9] After discussions with the Food and Drug Administration indicated that the obstacles to gaining approval were insurmountable, product development for beloranib was ended. [2]

Related Research Articles

Anti-obesity medication Class of pharmacological agents

Anti-obesity medication or weight loss medications are pharmacological agents that reduce or control weight. These medications alter one of the fundamental processes of the human body, weight regulation, by altering either appetite, or absorption of calories. The main treatment modalities for overweight and obese individuals remain dieting and physical exercise.

Fumagillin

Fumagillin is a complex biomolecule and used as an antimicrobial agent. It was isolated in 1949 from the microbial organism Aspergillus fumigatus.

Nilotinib

Nilotinib, sold under the brand name Tasigna marketed worldwide by Novartis, is a medication used to treat chronic myelogenous leukemia (CML) which has the Philadelphia chromosome. It may be used both in initial cases of chronic phase CML as well as in accelerated and chronic phase CML that has not responded to imatinib. It is taken by mouth.

Oleoyl-estrone

Oleoyl-estrone (OE), or estrone 3-oleate, is a fatty acid ester of estrone. It is a naturally circulating hormone in animals, including humans. It was studied as a potential weight-loss drug, but failed to show benefit in clinical trials. It was first reported in 1996 to cause a body fat loss effect in rats in the International Journal of Obesity and Related Metabolic Disorders. The animal research has all been conducted by the Nitrogen-Obesity Research Group of the University of Barcelona.

Dapagliflozin Diabetes medication

Dapagliflozin, sold under the brand names Farxiga (US) and Forxiga (EU) among others, is a medication used to treat type 2 diabetes. It is also used to treat adults with certain kinds of heart failure and chronic kidney disease.

Tesofensine Chemical compound

Tesofensine (NS2330) is a serotonin–noradrenaline–dopamine reuptake inhibitor from the phenyltropane family of drugs, which is being developed for the treatment of obesity. Tesofensine was originally developed by a Danish biotechnology company, NeuroSearch, who transferred the rights to Saniona in 2014.

Axitinib

Axitinib, sold under the brand name Inlyta, is a small molecule tyrosine kinase inhibitor developed by Pfizer. It has been shown to significantly inhibit growth of breast cancer in animal (xenograft) models and has shown partial responses in clinical trials with renal cell carcinoma (RCC) and several other tumour types.

Taranabant Chemical compound

Taranabant (codenamed MK-0364) is a cannabinoid receptor type 1 (CB1) inverse agonist that was investigated as a potential treatment for obesity due to its anorectic effects. It was discovered by Merck & Co.

Lestaurtinib

Lestaurtinib is a tyrosine kinase inhibitor structurally related to staurosporine. This semisynthetic derivative of the indolocarbazole K252a was investigated by Cephalon as a treatment for various types of cancer. It is an inhibitor of the kinases fms-like tyrosine kinase 3 (FLT3), Janus kinase 2 (JAK2), tropomyosin receptor kinase (trk) A (TrkA), TrkB and TrkC.

Lorcaserin Antiobesity drug

Lorcaserin, marketed under the brand name Belviq is a weight-loss drug developed by Arena Pharmaceuticals. It reduces appetite by activating a type of serotonin receptor known as the 5-HT2C receptor in a region of the brain called the hypothalamus, which is known to control appetite. It was removed from the market in the United States in 2020 due to an increased risk of cancer detected in users of Belviq.

Camostat Serine protease inhibitor

Camostat is a serine protease inhibitor. Serine protease enzymes have a variety of functions in the body, and so camostat has a diverse range of uses. Camostat is approved in Japan for the treatment of chronic pancreatitis and postoperative reflux esophagitis. The oral proteolytic enzyme inhibitor has been on the market since 1985 under the trade name Foipan Tablets. The manufacturer is Ono Pharmaceutical. The drug is used in the treatment of some forms of cancer and is also effective against some viral infections, as well as inhibiting fibrosis in liver or kidney disease or pancreatitis.

Ecopipam

Ecopipam is a dopamine antagonist which is under development for the treatment of Lesch-Nyhan syndrome, Tourette's syndrome, speech disorders, and restless legs syndrome. It is taken by mouth.

Bardoxolone methyl Chemical compound

Bardoxolone methyl is an experimental and orally-bioavailable semi-synthetic triterpenoid, based on the scaffold of the natural product oleanolic acid. Pre-clinical studies indicate that the compound acts as an activator of the Nrf2 pathway and an inhibitor of the NF-κB pathway. A phase 3 clinical trial evaluating bardoxolone methyl for the treatment of chronic kidney disease (CKD) was terminated in October 2012 after patients treated with the drug were found to have experienced a higher rate of heart-related adverse events, including heart failure, hospitalizations, and deaths.

Regorafenib, sold under the brand name Stivarga among others, is an oral multi-kinase inhibitor developed by Bayer which targets angiogenic, stromal and oncogenic receptor tyrosine kinase (RTK). Regorafenib shows anti-angiogenic activity due to its dual targeted VEGFR2-TIE2 tyrosine kinase inhibition. Since 2009 it was studied as a potential treatment option in multiple tumor types. By 2015 it had two US approvals for advanced cancers.

Brexpiprazole Atypical antipsychotic

Brexpiprazole, sold under the brand name Rexulti among others, is an atypical antipsychotic. It is a dopamine D2 receptor partial agonist and has been described as a "serotonin–dopamine activity modulator" (SDAM). The drug was approved by the U.S. Food and Drug Administration (FDA) on July 10, 2015, for the treatment of schizophrenia, and as an adjunctive treatment for depression. It has been designed to provide improved efficacy and tolerability (e.g., less akathisia, restlessness and/or insomnia) over established adjunctive treatments for major depressive disorder (MDD).

Sonidegib

Sonidegib (INN), sold under the brand name Odomzo, is a medication used to treat cancer.

SGLT2 inhibitors, also called gliflozins or flozins, are a class of medications that modulate sodium-glucose transport proteins in the nephron, unlike SGLT1 inhibitors that perform a similar function in the intestinal mucosa. The foremost metabolic effect of this is to inhibit reabsorption of glucose in the kidney and therefore lower blood sugar. They act by inhibiting sodium-glucose transport protein 2 (SGLT2). SGLT2 inhibitors are used in the treatment of type II diabetes mellitus (T2DM). Apart from blood sugar control, gliflozins have been shown to provide significant cardiovascular benefit in patients with type II diabetes (T2DM). Several medications of this class have been approved or are currently under development. In studies on canagliflozin, a member of this class, the medication was found to enhance blood sugar control as well as reduce body weight and systolic and diastolic blood pressure.

Setmelanotide

Setmelanotide, sold under the brand name Imcivree, is a medication used for the treatment of genetic obesity caused by a rare single-gene mutation.

Bisantrene

Bisantrene, trademarked as Zantrene, is an anthracenyl bishydrazone with anthracycline-like antineoplastic activity. Bisantrene intercalates with and disrupts the configuration of DNA, resulting in DNA single-strand breaks, DNA-protein crosslinking, and inhibition of DNA replication. This agent is similar to doxorubicin in activity, but unlike anthracyclines like doxorubicin, exhibits little cardiotoxicity.

Tirzepatide Neuropeptide analogue of gastric inhibitory polypeptide

Tirzepatide, sold under the brand name Mounjaro, is a medication used for the treatment of type 2 diabetes. Tirzepatide is given by subcutaneous injection. Common side effects may include nausea, vomiting, diarrhea, decreased appetite, constipation, upper abdominal discomfort, and abdominal pain.

References

  1. "News Release: Zafgen Secures $33 Million Series C Financing" (PDF). Zafgen, Inc. July 7, 2011. Archived from the original (PDF) on December 10, 2011.
  2. 1 2 "Zafgen Halts Development of Beloranib, to Cut Jobs by ~34%". nasdaq.com. July 20, 2016.
  3. Chun E, Han CK, Yoon JH, Sim TB, Kim YK, Lee KY (March 2005). "Novel inhibitors targeted to methionine aminopeptidase 2 (MetAP2) strongly inhibit the growth of cancers in xenografted nude model". International Journal of Cancer. 114 (1): 124–30. doi: 10.1002/ijc.20687 . PMID   15523682.
  4. Kim EJ, Shin WH (February 2005). "General pharmacology of CKD-732, a new anticancer agent: effects on central nervous, cardiovascular, and respiratory system". Biological & Pharmaceutical Bulletin. 28 (2): 217–23. doi: 10.1248/bpb.28.217 . PMID   15684472.
  5. "Zafgen Announces Positive Topline Phase 1b Data for ZGN-433 in Obesity". MedNews. Drugs.com. 5 January 2011.
  6. Hughes TE, Kim DD, Marjason J, Proietto J, Whitehead JP, Vath JE (September 2013). "Ascending dose-controlled trial of beloranib, a novel obesity treatment for safety, tolerability, and weight loss in obese women". Obesity. 21 (9): 1782–8. doi:10.1002/oby.20356. PMID   23512440. S2CID   2352854.
  7. Kim DD, Krishnarajah J, Lillioja S, de Looze F, Marjason J, Proietto J, et al. (June 2015). "Efficacy and safety of beloranib for weight loss in obese adults: a randomized controlled trial". Diabetes, Obesity & Metabolism. 17 (6): 566–572. doi:10.1111/dom.12457. PMID   25732625. S2CID   205076412.
  8. "Clinical Trials" . Retrieved 2014-11-18.
  9. "UPDATE 4-Zafgen halts obesity drug trial after second patient death". Reuters. 3 December 2015. Archived from the original on 2015-12-03. Retrieved 2015-12-03.