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Adjudin

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Adjudin

Adjudin
Systematic (IUPAC) name
1-(2,4-dichlorobenzyl)-1H-indazole-3-carbohydrazide
Clinical data
Legal status
  • Investigational new drug
Identifiers
CAS Registry Number  N
ATC code None
PubChem CID:
ChemSpider  Y
Chemical data
Formula C15H12Cl2N4O
Molecular mass 335.188 g/mol
 N   

Adjudin (AF-2364) is a drug which is under development as a potential non-hormonal male contraceptive drug, which acts by blocking the production of sperm in the testes, but without affecting testosterone production.[1] It is an analogue of the chemotherapy drug lonidamine, an indazole-carboxylic acid, and further studies continue to be conducted into this family of drugs as possible contraceptives.[2]

As of 1 May 2007, adjudin was in phase II human trials.[3]

As shown in mature male rats, the agent induces reversible germ cell loss from the seminiferous epithelium by disrupting cell adhesion function between Sertoli and germ cells.[4][5] It weakens the adhesion between the Sertoli cell and maturing sperm leading to a sloughing and loss of the latter.[6] As it does not affect spermatogonia themselves the loss of fertility is reversible. In experiments hormonal levels (FSH, LH, testosterone) were undisturbed during administration, and normal spermatogenesis returned in 95% of the tubules of rats at 210 days after the drug had been discontinued.[7]

When taken orally, the drug has very low bioavailability. The oral dose effective for contraception is so high that there have been side effects in the muscles and liver. Coupling an Adjudin molecule to a mutant form of follicle-stimulating hormone may solve this problem.[8] The mutant FSH is modified such that it no longer induces Inhibin B production, but the membrane-bound FSH receptors on Sertoli cells still bind to it, delivering the Adjudin directly to the target cells. The adjudin-FSH can be either injected, delivered in an implant, or as a gel.[9]

A study in 2013 indicated that Adjudin, similar to its analogue lonidamine, has properties that inhibit cancer growth by targeting mitochondria and blocking energy metabolism in certain kinds of tumor cells in mice, indicating that it has potential as a drug for cancer therapy.[10]

References

  1. ^ Mruk, DD (2008). "New perspectives in non-hormonal male contraception". Trends in endocrinology and metabolism: TEM 19 (2): 57–64.  
  2. ^ Tash, JS; Attardi, B; Hild, SA; Chakrasali, R; Jakkaraj, SR; Georg, GI (2008). "A novel potent indazole carboxylic acid derivative blocks spermatogenesis and is contraceptive in rats after a single oral dose". Biology of Reproduction 78 (6): 1127–38.  
  3. ^ Robert Finn (2007). "Male Contraceptive Methods Are in the Pipeline" (PDF). Ob. Gyn. News 42 (9): 28.  
  4. ^ Mruk, DD; Cheng, CY (2004). "Sertoli-Sertoli and Sertoli-germ cell interactions and their significance in germ cell movement in the seminiferous epithelium during spermatogenesis.". Endocrine Reviews 25 (5): 747–806.  
  5. ^ Lee, NP; Wong, EW; Mruk, DD; Cheng, CY (2009). "Testicular Cell Junction: A Novel Target for Male Contraception". Current medicinal chemistry 16 (7): 906–15.  
  6. ^ Cheng, CY; Mruk, D; Silvestrini, B; Bonanomi, M; Wong, CH; Siu, MK; Lee, NP; Lui, WY; Mo, MY (2005). "AF-2364 1-(2,4-dichlorobenzyl)-1H-indazole-3-carbohydrazide is a potential male contraceptive: a review of recent data". Contraception 72 (4): 251–61.  
  7. ^ Grima, J; Silvestrini, B; Cheng, CY (2001). "Reversible inhibition of spermatogenesis in rats using a new male contraceptive, 1-(2,4-dichlorobenzyl)-indazole-3-carbohydrazide". Biology of Reproduction 64 (5): 1500–8.  
  8. ^ Mruk, DD; Wong, CH; Silvestrini, B; Cheng, CY (2006). "A male contraceptive targeting germ cell adhesion". Nature Medicine 12 (11): 1323–8.  
  9. ^ http://malecontraceptives.org/methods/adjudin.php
  10. ^ Xie, QR; Liu, Y; Shao, J; Yang, J; Liu, T; Zhang, T; Wang, B; Mruk, DD; Silvestrini, B; Cheng, CY; Xia, W (2013). "Male contraceptive Adjudin is a potential anti-cancer drug". Biochemical Pharmacology 85 (3): 345–55.  

External links

  • "Trials for alternative male Pill show no side-effects" at the Independent
  • "Sperm-stopping male pill hope" at BBC News
  • Adjudin (a Lonidamine analogue) at MaleContraceptives.org
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