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 #
5U54HD042454-14
Application #
8894039
Study Section
Special Emphasis Panel (ZHD1-DRG-H)
Project Start
Project End
2016-06-30
Budget Start
2015-07-01
Budget End
2016-06-30
Support Year
14
Fiscal Year
2015
Total Cost
$266,630
Indirect Cost
$89,958
Name
University of Washington
Department
Type
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Rubinow, Katya B; Houston, Barbara; Wang, Shari et al. (2018) Androgen receptor deficiency in monocytes/macrophages does not alter adiposity or glucose homeostasis in male mice. Asian J Androl 20:276-283
Chen, Yan; Zhu, Jin-Yi; Hong, Kwon Ho et al. (2018) Structural Basis of ALDH1A2 Inhibition by Irreversible and Reversible Small Molecule Inhibitors. ACS Chem Biol 13:582-590
Paik, Jisun; Treuting, Piper M; Haenisch, Michael et al. (2018) Can inhibition of retinoic acid biosynthesis function as a non-hormonal female contraceptive? Contraception :
Sharma, Manju; Braun, Robert E (2018) Cyclical expression of GDNF is required for spermatogonial stem cell homeostasis. Development 145:
Rubinow, Katya B; Vaisar, Tomas; Chao, Jing H et al. (2018) Sex steroids mediate discrete effects on HDL cholesterol efflux capacity and particle concentration in healthy men. J Clin Lipidol 12:1072-1082
Haenisch, Michael; Treuting, Piper M; Brabb, Thea et al. (2018) Pharmacological inhibition of ALDH1A enzymes suppresses weight gain in a mouse model of diet-induced obesity. Obes Res Clin Pract 12:93-101
Berkseth, Kathryn E; Rubinow, Katya B; Melhorn, Susan J et al. (2018) Hypothalamic Gliosis by MRI and Visceral Fat Mass Negatively Correlate with Plasma Testosterone Concentrations in Healthy Men. Obesity (Silver Spring) 26:1898-1904
Swerdloff, Ronald S; Dudley, Robert E; Page, Stephanie T et al. (2017) Dihydrotestosterone: Biochemistry, Physiology, and Clinical Implications of Elevated Blood Levels. Endocr Rev 38:220-254
Ayoub, R; Page, S T; Swerdloff, R S et al. (2017) Comparison of the single dose pharmacokinetics, pharmacodynamics, and safety of two novel oral formulations of dimethandrolone undecanoate (DMAU): a potential oral, male contraceptive. Andrology 5:278-285
Rubinow, Katya B; Chao, Jing H; Hagman, Derek et al. (2017) Circulating sex steroids coregulate adipose tissue immune cell populations in healthy men. Am J Physiol Endocrinol Metab 313:E528-E539

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