Carboxylesterase Inhibitors: An Update.

Area of Science:

• Biochemistry
• Pharmacology

Background:

• Mammalian carboxylesterases (CES) are serine hydrolases crucial for metabolizing endogenous compounds and xenobiotics.
• CES1 and CES2 are the two primary human carboxylesterases with distinct physiological roles.
• CES1 is implicated in lipid metabolism, while CES2 activates prodrugs like capecitabine and CPT-11.

Purpose of the Study:

• To review recent advancements in the discovery and development of CES inhibitors.
• To summarize the inhibitory mechanisms and structure-activity relationships (SARs) of various CES inhibitors.
• To highlight the therapeutic potential of CES inhibitors in metabolic disorders and cancer treatment.

Main Methods:

• Comprehensive literature review of synthetic, semi-synthetic, and natural CES inhibitors.
• Analysis of inhibitory capacities and mechanisms against CES1 and CES2.
• Discussion of key structural features and SARs for CES1 and CES2 inhibitors.

Main Results:

• A wide array of CES inhibitors, including natural products and synthetic compounds, have been identified.
• Specific inhibitors demonstrate potential for treating hypertriglyceridaemia, obesity, and type 2 diabetes (CES1).
• CES2 inhibitors show promise in enhancing the efficacy and safety of anticancer prodrugs like CPT-11.

Conclusions:

• Carboxylesterases are significant targets for drug development due to their roles in metabolism and drug activation.
• Understanding SARs is critical for designing potent and selective CES inhibitors.
• Further research into CES inhibitors holds significant potential for biomedical applications.