Discovery and Development of Highly Potent and Orally Bioavailable Nonpeptidic α_vβ₆ Integrin Inhibitors

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Integrin Biology

Background:

• Alpha-v beta-6 (α_vβ₆) integrin is a therapeutic target for fibrotic diseases.
• Previous drug candidates were optimized for inhaled delivery, necessitating oral bioavailability improvements.

Purpose of the Study:

• To develop potent and orally bioavailable α_vβ₆ integrin inhibitors.
• To optimize drug properties by modifying aryl substituents and amine pKa for oral administration.

Main Methods:

• Synthesis and evaluation of 3-aryl((S)-3-fluoropyrrolidin-1-yl)butanoic acid derivatives.
• Pharmacokinetic profiling in rat, dog, and minipig models.
• Assessment of α_vβ₆ integrin binding potency (pIC50) and solubility.

Main Results:

• A novel compound, (S)-4-((S)-3-Fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)-3-(3-(2-methoxyethoxy)phenyl)butanoic acid, exhibited high potency (pIC50=8.0) and solubility (>2 mg/mL).
• The selected compound demonstrated favorable oral pharmacokinetics, including high bioavailability and low to moderate clearance across species.
• Estimated human dose range (10-75 mg b.i.d.) supports potential therapeutic application.

Conclusions:

• Successful development of orally bioavailable α_vβ₆ integrin inhibitors through medicinal chemistry optimization.
• The lead compound shows promise as a therapeutic agent for idiopathic pulmonary fibrosis.
• Further investigation is warranted for this novel class of integrin inhibitors.