Beloranib

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]

Beloranib
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
CAS Number
3D model (JSmol)
ChemSpider
PubChem CID
UNII
InChI
  • 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 N
    Key: ZEZFKUBILQRZCK-MJSCXXSSSA-N N
  • 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
SMILES
  • 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
Chemical formula
 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).
N verify (what is YN ?)
Infobox references

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]

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. "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.
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