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)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54HD042454-13
Application #
8726451
Study Section
Special Emphasis Panel (ZHD1)
Project Start
Project End
Budget Start
Budget End
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
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