Core Modifications of GSK3335103 toward Orally Bioavailable α_vβ₆ Inhibitors with Improved Synthetic Tractability

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Integrin Biology

Background:

• Alpha-v-beta-6 (α_vβ₆) integrin is a key target for treating fibrotic diseases due to its role in activating transforming growth factor-beta 1 (TGF-β₁).
• Developing orally bioavailable α_vβ₆ inhibitors is challenging because their pharmacophore must be zwitterionic to bind the RGD site.

Purpose of the Study:

• To design and develop a novel series of orally bioavailable α_vβ₆ inhibitors.
• To overcome synthetic challenges associated with previous inhibitors like GSK3008348 and GSK3335103.

Main Methods:

• Modification of existing α_vβ₆ inhibitors to reduce basicity and synthetic complexity.
• Optimization of lead compounds based on physicochemical and in vitro pharmacokinetic (PK) studies.
• Structure-activity relationship analysis to guide lead optimization.

Main Results:

• A new series of orally bioavailable α_vβ₆ inhibitors was successfully designed and developed.
• Lead molecules (S)-20 and 28 demonstrated potent α_vβ₆ inhibition.
• The developed inhibitors exhibit improved synthetic tractability compared to predecessors.

Conclusions:

• Novel orally bioavailable α_vβ₆ inhibitors with enhanced synthetic accessibility have been identified.
• These compounds represent promising drug candidates for the treatment of fibrotic diseases.
• The study highlights successful strategies for overcoming challenges in developing orally available integrin inhibitors.