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. doi: 10.1016/j.contraception.2005.03.008.

Abstract

Earlier studies have shown that 1-(2,4-dichlorobenzyl)-1H-indazole-3-carbohydrazide (AF-2364) is a potential male contraceptive when administered orally to adult Sprague-Dawley rats. This compound induces reversible germ cell loss from the seminiferous epithelium by disrupting cell adhesion function between Sertoli and germ cells, in particular, elongating/elongate/round spermatids and spermatocytes but not spermatogonia. Thus, this event is accompanied by a transient loss of fertility in treated rats. Once the drug is metabolically cleared, the remaining spermatogonia can begin repopulating the epithelium, and fertility bounces back. In this review, we summarize recent findings regarding the possible use of this drug for male contraception and its mechanism of action in the rat testis. We also provide an update on the efficacy results of using different treatment regimens in adult rats where AF-2364 was administered by gavage vs. intraperitoneal and intramuscular administration. These results have clearly indicated that AF-2364 is indeed a reversible male contraceptive. Furthermore, the tissue distribution in multiple organs and biological fluids using [3H]-AF-2364 is also reviewed. These data have clearly illustrated the low bioavailability of AF-2364 in rats and that this compound is not specifically taken up by any organs including the testis or the epididymis. These summaries are helpful to investigators in the field who seek to understand the molecular mechanism of action of AF-2364 in the rat testis and to explore its possible use for male contraception.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Biological Availability
  • Cell Adhesion / drug effects
  • Contraceptive Agents, Male*
  • Fertility / drug effects
  • Hydrazines* / administration & dosage
  • Hydrazines* / pharmacokinetics
  • Hydrazines* / pharmacology
  • Indazoles* / administration & dosage
  • Indazoles* / pharmacokinetics
  • Indazoles* / pharmacology
  • Male
  • Rats
  • Rats, Sprague-Dawley
  • Sertoli Cells / drug effects
  • Sertoli Cells / physiology
  • Spermatozoa / drug effects
  • Spermatozoa / physiology
  • Tissue Distribution

Substances

  • 1-(2,4-dichlorobenzyl)indazole-3-carbohydrazide
  • Contraceptive Agents, Male
  • Hydrazines
  • Indazoles