A Novel Potent Indazole Carboxylic Acid Derivative Blocks Spermatogenesis and Is Contraceptive in Rats after a Single Oral Dose1

Abstract

Women have historically been the focus for development of new contraceptive methods. The National Institutes of Health, World Health Organization, and Institute of Medicine have stressed the need to develop nonhormonal, nonsteroidal male contraceptive agents. We report results from initial dose-ranging studies of a new indazole carboxylic acid analogue, gamendazole. An infertility rate of 100% was achieved in seven out of seven proven-fertile male rats 3 wk after a single oral dose of 6 mg/kg of gamendazole. Fertility returned by 9 wk in four of seven animals, with typical numbers of normal-appearing conceptuses. A fertility rate of 100% returned in four of six animals that became infertile at a single oral dose of 3 mg/kg of gamendazole. No differences in mating behavior were observed in either of the gamendazole-treated groups versus the control (vehicle-only) group. In the animals that showed reversible infertility, a transient increase in circulating FSH levels coincided with an initial decline in inhibin B levels after administration of gamendazole, but no other significant changes in circulating reproductive hormones were observed. Gamendazole inhibited production of inhibin B by primary Sertoli cells in vitro with a median inhibitory concentration of 6.8 thorn+/- 3.0 (SEM) (3/4)x 10(-10) M, suggesting that Sertoli cells are a primary target. A biotinylated gamendazole analogue revealed cytoplasmic and perinuclear binding of gamendazole in primary Sertoli cells. Gamendazole represents the most potent new oral antispermatogenic indazole carboxylic acid to date. Our results, however, demonstrate that additional dose-finding studies are required to improve reversibility and widen the therapeutic window before more detailed drug development of this potential nonhormonal male contraceptive agent can occur.

Pleiotropic Impacts of Macrophage and Microglial Deficiency on Development in Rats with Targeted Mutation of the Csf1r Locus

“…This suggests that the alternative ligand, IL34, has a specific function in testis development in the rat. Consistent with that hypothesis, IL34 mRNA is highly-expressed in rat testis, and down-regulated by candidate male contraceptives (58).…”

New frontiers in nonhormonal male contraception

“…At this point, it remains to be determined if rodents, but not other mammals such as rabbits and dogs, are especially sensitive to compounds containing one or both of these chemical modifications, thereby resulting in death in some animals, as species differences can exist. Interestingly, lonidamine which contains a carboxylic acid group did not produce a single mortality as previously observed by us and recently reported by Tash et al [78]. Regardless, lonidamine is considered to be more toxic than adjudin; and while it is associated with several side effects, it is presently being used to kill tumor cells that have been sensitized by X-irradiation [85–87].…”

The biology of spermatogenesis: the past, present and future

“…These findings were subsequently confirmed by licensed toxicologists in different toxicity studies (Mruk et al 2006), as well as in recent studies from other laboratories (Tash et al 2008a;Sarkar & Mathur 2009). In essence, adjudin is the hydrazide form of lonidamine.…”

“…three out of five deaths representing a 60% mortality rate) was observed in rats treated with gamendazole at 200 mg kg 21 b.w. but not with adjudin in the same study (Tash et al 2008a). In the study on adjudin, two acute toxicity studies performed by licensed toxicologists using Introduction.…”

“…While 3 [H]adjudin was not specifically uptaken by the testis, it only perturbed cell adhesion in the testis, particularly at the apical ES, and induced premature release of elongating/elongated spermatids from the seminiferous epithelium (Chen et al 2003;Cheng et al 2005). These findings were subsequently confirmed by licensed toxicologists in different toxicity studies (Mruk et al 2006), as well as in recent studies from other laboratories (Tash et al 2008a;Sarkar & Mathur 2009). In essence, adjudin is the hydrazide form of lonidamine.…”