Adjudin

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Adjudin
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Systematic (IUPAC) name
1-(2,4-dichlorobenzyl)-1H-indazole-3-carbohydrazide
Legal status
Legal status
  • Investigational new drug
Identifiers
CAS Number 252025-52-8
ATC code none
PubChem CID 9819086
Chemical data
Formula C15H12Cl2N4O
Molar mass 335.188 g/mol[[Script error: No such module "String".]]
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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 (2007 -05-01), 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.

References

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External links


es:Adjudin
  1. ↑ Mruk DD. New perspectives in non-hormonal male contraception. Trends in Endocrinology and Metabolism. 2008 Mar;19(2):57-64. PMID 18291665
  2. ↑ Tash JS, Attardi B, Hild SA, Chakrasali R, Jakkaraj SR, Georg GI. A novel potent indazole carboxylic acid derivative blocks spermatogenesis and is contraceptive in rats after a single oral dose. Biology of Reproduction. 2008 Jun;78(6):1127-38. PMID 18218612
  3. ↑ Robert Finn. "Male Contraceptive Methods Are in the Pipeline". Ob.Gyn. News 42:28, May 1, 2007.  Full text PDF
  4. ↑ Dolores D. Mruk and C. Yan Cheng. Sertoli-Sertoli and Sertoli-Germ Cell Interactions and Their Significance in Germ Cell Movement in the Seminiferous Epithelium during Spermatogenesis. Endocrine Reviews (2004) 25 (5): 747-806
  5. ↑ Lee NP, Wong EW, Mruk DD, Cheng CY. Testicular cell junction: a novel target for male contraception. Current Medicinal Chemistry. 2009;16(7):906-15. PMID 19275601
  6. ↑ Cheng CY, Mruk D, Silvestrini B, Bonanomi M, Wong CH, Siu MK, Lee NP, Lui WY, Mo MY. AF-2364 [1-(2,4-dichlorobenzyl)-1H-indazole-3-carbohydrazide] is a potential male contraceptive: a review of recent data. Contraception. 2005 Oct;72(4):251-61. PMID 16181968
  7. ↑ Grima J, Silvestrini B, Cheng CY. Reversible inhibition of spermatogenesis in rats using a new male contraceptive, 1-(2,4-dichlorobenzyl)-indazole-3-carbohydrazide. Biol. Reprod. 2001 May;64(5):1500-8. PMID 11319158
  8. ↑ Future male 'pill' targets testicles New Scientist, 29 October 2006, citing Mruk DD, Wong CH, Silvestrini B, Cheng CY. A male contraceptive targeting germ cell adhesion. Nature Medicine. 2006 Nov;12(11):1323-8. PMID 17072312
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