We recently demonstrated that bisdichloroacetyldiamines (BDADs) function as oral, reversible, non-hormonal male contraceptives by inhibifing testicular retinoic acid biosynthesis and, subsequently, spermatogenesis. Retinoic iacid is produced in the testes by the enzyme aldehyde dehydrogenase-1 a2 (ALDH1A2). Unfortunately, BDADs are promiscuous inhibitors of several ALDH isozymes;therefore, BDAD administration leads to unacceptable side effects. In this proposal, we aim to develop novel specific inhibitors of ALDH1A2 that can exert contraceptive effects without affecting ALDH activity in other tissues. We recently screened a library of 60,000 small "drug-like" molecules and identified 300 potential inhibitors of ALDH1A2, each with an IC50 (concentration at which enzyme activity is reduced by more than 50%) of less than 3uM.
In Aims #1 and Aim #2 of this proposal, we will identify and develop the most promising of these compounds, and optimize their potency, selectivity and pharmaceutical and pharmacokinetic characteristics. To accomplish this, we will use X-ray crystallography and computer-guided chemical modifications. In vitro absorption, distribution and metabolism (ADME) testing and in vivo pharmacokinetic studies.
In Aim #3 of this proposal, we will test the ability of the most promising inhibitors to suppress spermatogenesis and fertility in mice. This is multidisciplinary work with a high potential for translation to clinical trials. The proposed experiments will identify and develop novel specific inhibitors of ALDH1A2 for male contraception, work that we believe will allow for safe, effective, oral, non-hormonal male contraception and finally bring the dream of a "male pill" to fruition.
Thirty percent of all contraception in the US is male-directed, consisting of condoms and vasectomy. Most men would be interested in a reversible contraceptive analogous to the female pill. We have demonstrated that blocking vitamin A function reversibly suppresses sperm production. Our research is directed towards developing a safe, oral medicine to block vitamin A function only in the testes, something we believe will allow for the introduction of a male contraceptive pill.
|Cooper, Lori A; Page, Stephanie T (2014) Androgens and prostate disease. Asian J Androl 16:248-55|
|Surampudi, P; Page, S T; Swerdloff, R S et al. (2014) Single, escalating dose pharmacokinetics, safety and food effects of a new oral androgen dimethandrolone undecanoate in man: a prototype oral male hormonal contraceptive. Andrology 2:579-87|
|Chao, Jing; Page, Stephanie T; Anderson, Richard A (2014) Male contraception. Best Pract Res Clin Obstet Gynaecol 28:845-57|
|Amory, John K; Hong, SungWoo; Yu, Xiaozhong et al. (2014) Melphalan, alone or conjugated to an FSH-? peptide, kills murine testicular cells in vitro and transiently suppresses murine spermatogenesis in vivo. Theriogenology 82:152-9|
|Chakraborty, Papia; Buaas, F William; Sharma, Manju et al. (2014) LIN28A marks the spermatogonial progenitor population and regulates its cyclic expansion. Stem Cells 32:860-73|
|Amory, John K; Arnold, Samuel; Lardone, María C et al. (2014) Levels of the retinoic acid synthesizing enzyme aldehyde dehydrogenase-1A2 are lower in testicular tissue from men with infertility. Fertil Steril 101:960-6|
|Paik, Jisun; Haenisch, Michael; Muller, Charles H et al. (2014) Inhibition of retinoic acid biosynthesis by the bisdichloroacetyldiamine WIN 18,446 markedly suppresses spermatogenesis and alters retinoid metabolism in mice. J Biol Chem 289:15104-17|
|Roth, Mara Y; Shih, Grace; Ilani, Niloufar et al. (2014) Acceptability of a transdermal gel-based male hormonal contraceptive in a randomized controlled trial. Contraception 90:407-12|
|Anawalt, Bradley D (2013) Approach to male infertility and induction of spermatogenesis. J Clin Endocrinol Metab 98:3532-42|
|Roth, M Y; Nya-Ngatchou, J J S; Lin, K et al. (2013) Androgen synthesis in the gonadotropin-suppressed human testes can be markedly suppressed by ketoconazole. J Clin Endocrinol Metab 98:1198-206|
Showing the most recent 10 out of 73 publications