Lp-PLA2 inhibitors (GlaxoSmithKline)

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Biotechnology

Background:

• Atherosclerosis is a significant cardiovascular disease.
• Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is implicated in atherosclerosis pathogenesis.
• Inhibiting Lp-PLA(2) is a therapeutic strategy for atherosclerosis.

Purpose of the Study:

• To investigate substituted pyrimidin-4-ones as reversible inhibitors of Lp-PLA(2).
• To evaluate SB-435495, a specific compound in this series, for potential atherosclerosis treatment.
• To advance the development of novel Lp-PLA(2) inhibitors.

Main Methods:

• Discovery of SB-435495 utilizing gene technology from Human Genome Sciences (HGS).
• Development of a series of reversible pyrimidin-4-one inhibitors.
• Development of irreversible inhibitors, including SB-222657 and SB-253514 derivatives.
• Initiation of Phase II clinical trials for SB-435495.

Main Results:

• SB-435495 identified as a reversible inhibitor of Lp-PLA(2).
• Development of both reversible and irreversible Lp-PLA(2) inhibitors.
• Progression of SB-435495 into Phase II clinical trials.

Conclusions:

• Substituted pyrimidin-4-ones represent a promising class of reversible Lp-PLA(2) inhibitors.
• SB-435495 shows potential for the treatment of atherosclerosis.
• Further clinical investigation of SB-435495 is warranted.