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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54HD042454-13
Application #
8726451
Study Section
Special Emphasis Panel (ZHD1)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
13
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Washington
Department
Type
DUNS #
City
Seattle
State
WA
Country
United States
Zip Code
98195
Griswold, Michael D (2016) Spermatogenesis: The Commitment to Meiosis. Physiol Rev 96:1-17
Kocarnik, Beverly M; Boyko, Edward J; Matsumoto, Alvin M et al. (2016) Baseline estradiol concentration in community-dwelling Japanese American men is not associated with intra-abdominal fat accumulation over 10 years. Obes Res Clin Pract 10:624-632
Arnold, Samuel L; Stevison, Faith; Isoherranen, Nina (2016) Impact of Sample Matrix on Accuracy of Peptide Quantification: Assessment of Calibrator and Internal Standard Selection and Method Validation. Anal Chem 88:746-53
Chao, Jing; Rubinow, Katya B; Kratz, Mario et al. (2016) Short-Term Estrogen Withdrawal Increases Adiposity in Healthy Men. J Clin Endocrinol Metab 101:3724-3731
Chen, Yao; Ma, Li; Hogarth, Cathryn et al. (2016) Retinoid signaling controls spermatogonial differentiation by regulating expression of replication-dependent core histone genes. Development 143:1502-11
Roth, M Y; Page, S T; Bremner, W J (2016) Male hormonal contraception: looking back and moving forward. Andrology 4:4-12
Lee, Ada P; Roth, Mara Y; Nya-Ngatchou, Jean-Jacques et al. (2016) Testicular fine-needle aspiration for the assessment of intratesticular hormone concentrations. Asian J Androl 18:21-4
Roth, Mara Y; Amory, John K (2016) Beyond the Condom: Frontiers in Male Contraception. Semin Reprod Med 34:183-90
Amory, John K (2016) Male contraception. Fertil Steril 106:1303-1309
Kent, Travis; Arnold, Samuel L; Fasnacht, Rachael et al. (2016) ALDH Enzyme Expression Is Independent of the Spermatogenic Cycle, and Their Inhibition Causes Misregulation of Murine Spermatogenic Processes. Biol Reprod 94:12

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