# Optimization of in vivo validated ADCY10 inhibitors

> **NIH NIH P50** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $395,552

## Abstract

Project 1
Sperm must be motile and complete capacitation to be able to fertilize the oocyte. Soluble adenylyl cyclase
(sAC) is an enzyme in sperm that is essential for both processes. sAC knockout mice are male specific
sterile, and men with mutations which disrupt sAC are infertile. In both mice and men, all other phenotypes
observed require long periods of sAC absence to manifest. Thus, an acutely acting sAC inhibitor could be
a safe and effective on-demand contraceptive by blocking sperm functions for hours without eliciting the
side effects only seen when sAC is absent for months or years. Such a male birth control pill would only
be taken when, and as often, as needed, shortly before sex. The goal of the Weill Cornell Medicine
Contraception Research Center (WCM-CRC) is to develop acutely acting sAC inhibitors into on-demand
birth control pills. This Contraception Development Research Project focuses on advancing the in vivo
validated chemical series of sAC inhibitors which demonstrated proof-of-concept for on-demand male
contraception in mice. A `tool' compound from this series renders male mice temporarily infertile. In this
project, we propose lead optimization to enhance pharmacokinetic properties while maintaining (or
improving) potency, drug-like properties, and other efficacy-defining features. The goal of these studies is
a series of well-developed, potent, selective, drug-like, non-toxic, orally available sAC inhibitors with better
pharmacokinetic profiles to progress into in vivo animal testing (Project 2 of the WCM-CRC). Our ultimate
goal is to advance optimized leads into clinical development candidates suitable for an FDA Investigational
New Drug (IND) application to test a novel oral, nonhormonal contraceptive for men.

## Key facts

- **NIH application ID:** 10904992
- **Project number:** 5P50HD113015-02
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** LONNY R LEVIN
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $395,552
- **Award type:** 5
- **Project period:** 2023-08-10 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10904992

## Citation

> US National Institutes of Health, RePORTER application 10904992, Optimization of in vivo validated ADCY10 inhibitors (5P50HD113015-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10904992. Licensed CC0.

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