# Development of new ADCY10 inhibitors

> **NIH NIH P50** · WEILL MEDICAL COLL OF CORNELL UNIV · 2021 · $520,104

## Abstract

Project 2
Freshly ejaculated mammalian sperm are unable to fertilize an egg. They acquire fertilizing
capacity in the hours following ejaculation, as they pass through the female reproductive tract, in
a process known as capacitation. Soluble adenylyl cyclase (sAC: ADCY10) is a non-hormonal
target essential for sperm capacitation and male fertility. Pharmacological sAC inhibitors block
sperm functions in vitro and two distinct sAC knockout (KO) mouse strains exhibit male-specific
sterility without exhibiting other overt phenotypes. The overall hypothesis tested in this
Contraception Research Center (CRC) is that sAC inhibitors can be designed which can be
appropriately dosed to block sperm functions while minimizing undesirable side effects. In Project
1, we embark on in vivo studies of an already developed series of potent, selective sAC inhibitors.
In this Contraception Development Research Project, we will develop additional leads, based
upon distinct structurally and biochemically validated scaffolds. Specifically, we will (1) design
new chemical series by fragment-based drug design (FBDD) and structure-based drug design
(SBDD) using available co-crystal structures of sAC with various inhibitors; (2) synthesize and
test small panels of derivatives of these new chemical structures; and (3) use medicinal chemistry
and structural biology to refine the compounds into inhibitors with improved potency, selectivity,
and drug-like properties. Suitable alternative sAC inhibitors will be subjected to the pipeline of
refinement cycles and in vivo studies described in Project 1 of this CRC. The ultimate goal of this
Project is to develop sAC inhibitors as lead compounds for oral, non-hormonal contraceptives.

## Key facts

- **NIH application ID:** 10144841
- **Project number:** 5P50HD100549-03
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** JOCHEN BUCK
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $520,104
- **Award type:** 5
- **Project period:** 2019-09-12 → 2022-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10144841

## Citation

> US National Institutes of Health, RePORTER application 10144841, Development of new ADCY10 inhibitors (5P50HD100549-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10144841. Licensed CC0.

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