Structure-Based Discovery of Proline-Derived Arginase Inhibitors with Improved Oral Bioavailability for...

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Drug Discovery

Background:

• Arginase (ARG) inhibition shows therapeutic potential for pulmonary disease, vascular disease, and cancer.
• Selective small molecule ARG inhibitors with oral bioavailability are in high demand.
• Previous ARG inhibitors faced challenges due to unique physicochemical properties.

Purpose of the Study:

• To discover novel, potent, and orally bioavailable small molecule arginase inhibitors.
• To overcome challenges associated with previous arginase inhibitor physicochemical properties.
• To identify drug candidates with favorable druglike properties for therapeutic applications.

Main Methods:

• Structure-based drug design was employed.
• A focused optimization strategy was utilized.
• A class of boronic acids featuring a proline scaffold was discovered.

Main Results:

• Novel boronic acid inhibitors with superior potency and oral bioavailability were identified.
• Compounds 4a, 18, and 27 demonstrated a favorable overall profile.
• Inhibitor 4a was well-tolerated in a mouse carcinoma model at effective concentrations.

Conclusions:

• Boronic acids with a proline scaffold represent a promising class of arginase inhibitors.
• These inhibitors possess superior potency and oral bioavailability compared to previous agents.
• Further development of these compounds may lead to new treatments for various diseases.