Heterobiaryl and heterobiaryl ether derived M5 positive allosteric modulators.

Area of Science:

• Medicinal Chemistry
• Neuroscience
• Pharmacology

Background:

• Muscarinic acetylcholine receptors (mAChRs) are key targets for neurological disorders.
• Previous work identified VU0119498 as a pan G(q) mAChR M(1), M(3), M(5) positive allosteric modulator (PAM).
• There was a need for M(5)-selective modulators to probe receptor function.

Purpose of the Study:

• To describe the lead optimization of VU0238429, the first M(5)-preferring PAM.
• To improve the physiochemical properties of M(5)-preferring PAMs.
• To explore structure-activity relationships for selective mAChR modulation.

Main Methods:

• Iterative parallel synthesis was employed.
• Basic heterocycles were incorporated into the chemical structure.
• Analog work around VU0119498 guided the optimization campaign.

Main Results:

• VU0238429 was identified as an M(5)-preferring PAM.
• Chemical modifications led to improved physiochemical characteristics.
• The study established a foundation for developing M(5)-selective mAChR modulators.

Conclusions:

• Lead optimization successfully yielded VU0238429, a novel M(5)-preferring PAM.
• The synthetic strategy enabled the improvement of key drug-like properties.
• This research provides valuable tools for investigating M(5) receptor pharmacology.