# On-demand nonhormonal male contraception via ADCY10 inhibition

> **NIH NIH P50** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $1,999,520

## Abstract

Overall
Mammalian sperm are stored in the epididymis in a dormant state; they are immotile and unable to fertilize
the egg. Upon ejaculation, sperm begin swimming and initiate a process called capacitation, where they
become competent to fertilize the oocyte. An initial event in capacitation and activation of motility is the
bicarbonate-induced stimulation of soluble adenylyl cyclase (sAC: ADCY10). Men and male mice with the
sAC gene knocked out are infertile, and in vivo administration of sAC inhibitors to male mice prevents
sperm motility and renders the males temporarily infertile. Thus, sAC is a nonhormonal target, genetically
and pharmacologically validated to be essential for male fertility. Besides male-specific sterility, the only
other phenotypes of sAC knockout men or mice are dependent upon chronic loss of sAC for extended
periods of time. We propose to leverage acutely acting inhibitors, whose effects will be transient, to avoid
mechanism-based side effects and limit the inherent perils associated with chronic dosing. The goal of the
Weill Cornell Medicine Contraceptive Research Center (WCM-CRC) is to develop acutely acting sAC
inhibitors into safe and effective nonhormonal, orally available, on-demand contraceptives which men take
only when and as often as needed, shortly before sex. In two Contraceptive Development Research
Projects, we propose to improve binding affinity, pharmacokinetics (including oral bioavailability), drug-like
characteristics, and safety of sAC inhibitors with the expectation that pharmacokinetic parameters can be
optimized to balance efficacy with minimal adverse effects. In Project 1, we focus on a chemical series
validated in vivo in a preclinical animal model, and in Project 3, we propose to develop additional leads
from structurally distinct scaffolds. In Project 2, we will establish a second, non-rodent animal model for
testing contraceptive efficacy; test the in vivo efficacy of optimized sAC inhibitors; and validate sperm
motility as a pharmacodynamic biomarker of efficacy for use in early phase clinical trials of an on-demand
male contraceptive. A major goal of the WCM-CRC is to identify a clinical lead candidate (along with
backups) to advance into Investigational New Drug (IND) enabling studies for a novel oral, nonhormonal
contraceptive for men.

## Key facts

- **NIH application ID:** 10904987
- **Project number:** 5P50HD113015-02
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** JOCHEN BUCK
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,999,520
- **Award type:** 5
- **Project period:** 2023-08-10 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10904987

## Citation

> US National Institutes of Health, RePORTER application 10904987, On-demand nonhormonal male contraception via ADCY10 inhibition (5P50HD113015-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10904987. Licensed CC0.

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