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

Department of Molecular and Integrative Physiology⁴ and Interdisciplinary Center for Male Contraceptive Research and Drug Development,⁵ University of Kansas Medical Center, Kansas City, Kansas 66160 BIOQUAL, Inc.,⁶ Rockville, Maryland 20850-3336 Department of Medicinal Chemistry,⁷ University of Kansas, Lawrence, Kansas 66045-7582

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 þ± 3.0 (SEM) 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.

fertilization, male contraception, Sertoli cells, spermatogenesis, testis

³Current address: Department of Medicinal Chemistry, 717 Delaware Street SE, University of Minnesota, Minneapolis, MN 55414.

¹Supported by National Institutes of Health (NIH) U54 HD-055763 (to J.S.T.), NIH N01 HD1–3313 (to G.I.G.), and U54 HD33994 Center for Reproductive Sciences, a National Institute of Child Health and Human Development (NICHD) Grant for Specialized Cooperative Centers Program in Reproductive Research (SCCPRR), at the University of Kansas Medical Center. Also supported by NICHD contract N01-HD-2-3338 awarded to BIOQUAL, Inc. Dedicated to the memory of Geoffrey M.H. Waites, Sc.D., Ph.D. and Thaddeus R.R. Mann, M.D., Ph.D., Sc.D., F.R.S.

Correspondence: ²FAX: 913 588 7180; e-mail: jtash{at}kumc.edu