Plasma Protein Binding as an Optimizable Parameter for Acidic Drugs.

Area of Science:

• Pharmacology
• Drug Discovery
• Medicinal Chemistry

Background:

• Acidic molecules often have low distribution volumes, requiring low clearance (CL) for effective half-life.
• Plasma protein binding (PPB) is typically not optimized, but can be leveraged for acidic drugs.
• Increasing PPB can maintain a low distribution volume and reduce CL by limiting drug access to organs.

Purpose of the Study:

• To explore the optimization of plasma protein binding (PPB) for acidic drug candidates.
• To detail the development of acidic CXC chemokine receptor 2 (CXCR2) antagonists for inflammatory diseases.
• To demonstrate how modulating PPB can enhance effective half-life for oral drug delivery.

Main Methods:

• Optimization of acidic CXC chemokine receptor 2 (CXCR2) antagonists.
• Investigated the relationship between plasma protein binding (PPB), clearance (CL), and volume of distribution (Vss).
• Evaluated drug candidates AZD5069 and AZD4721 for oral bioavailability and pharmacokinetic properties.

Main Results:

• Developed orally bioavailable acidic CXCR2 antagonists AZD5069 and AZD4721.
• Achieved low intrinsic clearance (<5 µl/min per 10^6 cells) and volume of distribution (<0.3 L/kg).
• Attained effective half-lives of 4 hours (AZD5069) and 17 hours (AZD4721) in humans.

Conclusions:

• Modulating plasma protein binding (PPB) is a viable strategy to optimize effective half-life in drug discovery.
• High pharmacologic potency is crucial for successful PPB-based half-life optimization.
• This approach led to the clinical advancement of novel oral treatments for inflammatory diseases.