# ALDH1A1/A2 Inhibitors for Male Contraception

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2020 · $382,563

## Abstract

Bisdichloroacetyldiamines such as WIN 18,446 function as oral, reversible, non-hormonal male contraceptives
by inhibiting testicular retinoic acid biosynthesis and, subsequently, spermatogenesis. Retinoic acid is
produced in the germ cells by the enzymes aldehyde dehydrogenase-1A1 and 1A2 (ALDH1A1/1A2), which are
potently inhibited by WIN 18,446. Unfortunately, WIN 18,446 also inhibits aldehyde dehydrogenase-2, leading
to disulfiram reactions when administration of WIN 18,446 is combined with alcohol. In this proposal, we will
develop novel specific inhibitors of ALDH1A1/1A2 that can exert contraceptive effects without inhibiting
ALDH2. We have developed several potent and specific inhibitors of ALDH1A1/1A2, and tested them
extensively in vitro and in vivo. The two current lead scaffolds are selective for ALDH1A1/1A2 with IC50s of
<200 nM and do not inhibit ALDH2. However, they are currently not as effective as BDADs at suppressing
spermatogenesis due to sub-optimal pharmaceutical properties. In Aims #1 of this proposal, we will optimize
the potency, selectivity, solubility and pharmaceutical characteristics of our inhibitors using computer-guided
chemical modifications based upon the our recently solved X-ray co-crystallographic structure of the inhibitors
in the ALDH1A substrate binding site. In Aim #2 we will conduct in vitro testing (solubility, absorption and
metabolism) and in vivo pharmacokinetic and pharmacodynamic studies to determine the best inhibitor for
testing as a male contraceptive. In Aim #3 of this proposal, we will test the ability of the most promising
inhibitors to suppress spermatogenesis and fertility in mice. If successful, the proposed experiments will result
in novel specific inhibitors of ALDH1A1/1A2 for male contraception and lead to an effective, oral, non-hormonal
male contraceptive, finally bringing the dream of a “male pill” to fruition.

## Key facts

- **NIH application ID:** 10020794
- **Project number:** 5R01HD098039-02
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** John K. Amory
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $382,563
- **Award type:** 5
- **Project period:** 2019-09-13 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10020794

## Citation

> US National Institutes of Health, RePORTER application 10020794, ALDH1A1/A2 Inhibitors for Male Contraception (5R01HD098039-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10020794. Licensed CC0.

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