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BAY-9835: Discovery of the First Orally Bioavailable ADAMTS7 Inhibitor.

Daniel Meibom¹, Pierre Wasnaire¹, Kristin Beyer¹

¹Bayer AG, 42113 Wuppertal, Germany.

Journal of Medicinal Chemistry

|February 13, 2024

Summary

Researchers developed BAY-9835, the first orally bioavailable inhibitor targeting ADAMTS7 (a key enzyme in coronary artery disease). This discovery offers a new therapeutic avenue for cardiovascular conditions.

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Area of Science:

Biochemistry and Medicinal Chemistry
Cardiovascular Disease Research
Drug Discovery and Development

Background:

ADAMTS7, a matrix metalloprotease, is implicated in coronary artery disease (CAD) development via genome-wide association studies.
The enzyme's proteolytic activity is crucial in atherogenesis and restenosis following vascular injury.

Purpose of the Study:

To design and optimize novel inhibitors targeting the catalytic domain of ADAMTS7.
To develop an orally bioavailable ADAMTS7 inhibitor for potential therapeutic applications in cardiovascular diseases.

Main Methods:

In silico design of ADAMTS7 inhibitors based on existing ADAMTS4/ADAMTS5 inhibitors.
Structure-guided optimization using X-ray crystallography to enhance selectivity against MMP12.
Chemical modification, including the incorporation of 5-membered heteroaromatic groups, to improve potency.
Pharmacokinetic (DMPK) property fine-tuning to achieve oral bioavailability.

Main Results:

Initial inhibitors showed limited selectivity against MMP12.
Exploiting binding site differences between ADAMTS7 and MMP12 significantly improved selectivity.
Optimization led to potent ADAMTS7 inhibition and favorable DMPK properties.
BAY-9835 was identified as the first orally bioavailable ADAMTS7 inhibitor.

Conclusions:

BAY-9835 represents a significant advancement as the first orally bioavailable ADAMTS7 inhibitor.
The study demonstrates a successful structure-based drug design strategy for targeting ADAMTS7.
Further optimization for selectivity against ADAMTS12 is feasible, indicating continued therapeutic potential.