Fertilysin

Fertilysin
Clinical data
Other names	WIN 18446
Identifiers
	IUPAC name 2,2-Dichloro-N-[8-[(2,2-dichloroacetyl)amino]octyl]acetamide;
CAS Number	1477-57-2;
PubChem CID	15134;
ChemSpider	14405;
UNII	3F56RA64JN;
ChEBI	CHEBI:90441;
ChEMBL	ChEMBL3276621;
CompTox Dashboard (EPA)	DTXSID80163783 ;
ECHA InfoCard	100.014.576
Chemical and physical data
Formula	C12H20Cl4N2O2
Molar mass	366.10 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES ClC(C(NCCCCCCCCNC(C(Cl)Cl)=O)=O)Cl;
	InChI InChI=1S/C12H20Cl4N2O2/c13-9(14)11(19)17-7-5-3-1-2-4-6-8-18-12(20)10(15)16/h9-10H,1-8H2,(H,17,19)(H,18,20); Key:FAOMZVDZARKPFJ-UHFFFAOYSA-N;

Fertilysin (WIN 18446) is an experimental drug that was studied as a male contraceptive, but was never marketed. It interferes with testicular production of retinoic acid,^[1] which is necessary for spermatogenesis. In studies in male animals including rodents, wolves, cats, and shrews, fertilysin was found to be a safe, effective, and reversible oral contraceptive.^[2]^[3] However, the side effects observed in human clinical trials preclude its use in men.^[4]

Fertilysin was originally studied in the 1950s for its potential amebicidal effects.^[4]^[5]^[6] When the anti-spermatogenesis effects were observed in animal studies, the focus of the research turned towards its potential use as a contraceptive. Fertilysin is an inhibitor of aldehyde dehydrogenase 1a2, a member of the aldehyde dehydrogenase family of enzymes. Inhibition of this enzyme blocks the production of retinoic acid which prevents the production of sperm. Because aldehyde dehydrogenases are also involved in the metabolism of ethanol, fertilysin has side effects similar to the action of disulfiram (Antabuse).^[3] Fertilysin may also have teratogenic effects.^[7]

References

^ Paik J, Haenisch M, Muller CH, Goldstein AS, Arnold S, Isoherranen N, et al. (May 2014). "Inhibition of retinoic acid biosynthesis by the bisdichloroacetyldiamine WIN 18,446 markedly suppresses spermatogenesis and alters retinoid metabolism in mice". The Journal of Biological Chemistry. 289 (21): 15104–15117. doi:10.1074/jbc.M113.540211. PMC 4031560. PMID 24711451.
^ Heller CG, Moore DJ, Paulsen CA (January 1961). "Suppression of spermatogenesis and chronic toxicity in men by a new series of bis(dichloroacetyl) diamines". Toxicology and Applied Pharmacology. 3: 1–11. doi:10.1016/0041-008x(61)90002-3. PMID 13713106.
^ ^a ^b "Fertilysin". Inxight Drugs. National Center for Advancing Translational Sciences (NCAT): U.S. National Institutes of Health.
^ ^a ^b Kean S (April 20, 2021). "Why Don't We Have a Male Birth Control Pill Yet?". Science History Institute.
^ Berberian DA, Slighter RG, Dennis EW (1961). "N,N′-bis(Dichloroacetyl)Diamines as Amebicidal Agents". The American Journal of Tropical Medicine and Hygiene. 10 (4): 503–509. doi:10.4269/ajtmh.1961.10.503.
^ Coulston F, Beyler AL, Drobeck HP (November 1960). "The biologic actions of a new series of bis(dichloroacetyl) diamines". Toxicology and Applied Pharmacology. 2 (6): 715–731. doi:10.1016/0041-008X(60)90088-0. PMID 13695940.
^ Binder M (February 1985). "The teratogenic effects of a bis(dichloroacetyl)diamine on hamster embryos. Aortic arch anomalies and the pathogenesis of the DiGeorge syndrome". The American Journal of Pathology. 118 (2): 179–193. PMC 1887872. PMID 3970137.

[1] Paik J, Haenisch M, Muller CH, Goldstein AS, Arnold S, Isoherranen N, et al. (May 2014). "Inhibition of retinoic acid biosynthesis by the bisdichloroacetyldiamine WIN 18,446 markedly suppresses spermatogenesis and alters retinoid metabolism in mice". The Journal of Biological Chemistry. 289 (21): 15104–15117. doi:10.1074/jbc.M113.540211. PMC 4031560. PMID 24711451.

[2] Heller CG, Moore DJ, Paulsen CA (January 1961). "Suppression of spermatogenesis and chronic toxicity in men by a new series of bis(dichloroacetyl) diamines". Toxicology and Applied Pharmacology. 3: 1–11. doi:10.1016/0041-008x(61)90002-3. PMID 13713106.

[Inxight-3] "Fertilysin". Inxight Drugs. National Center for Advancing Translational Sciences (NCAT): U.S. National Institutes of Health.

[sciencehistory-4] Kean S (April 20, 2021). "Why Don't We Have a Male Birth Control Pill Yet?". Science History Institute.

[5] Berberian DA, Slighter RG, Dennis EW (1961). "N,N′-bis(Dichloroacetyl)Diamines as Amebicidal Agents". The American Journal of Tropical Medicine and Hygiene. 10 (4): 503–509. doi:10.4269/ajtmh.1961.10.503.

[6] Coulston F, Beyler AL, Drobeck HP (November 1960). "The biologic actions of a new series of bis(dichloroacetyl) diamines". Toxicology and Applied Pharmacology. 2 (6): 715–731. doi:10.1016/0041-008X(60)90088-0. PMID 13695940.

[7] Binder M (February 1985). "The teratogenic effects of a bis(dichloroacetyl)diamine on hamster embryos. Aortic arch anomalies and the pathogenesis of the DiGeorge syndrome". The American Journal of Pathology. 118 (2): 179–193. PMC 1887872. PMID 3970137.

[1]

[2]

[3]

[4]

[5]

[6]

[7]