Discovery libraries targeting the major enzyme classes: the serine hydrolases

Area of Science:

• Medicinal Chemistry
• Enzyme Inhibition

Background:

• Serine hydrolases are crucial drug targets.
• Fatty acid amide hydrolase (FAAH) plays a role in various physiological processes.
• Developing selective inhibitors for serine hydrolases is an ongoing challenge.

Purpose of the Study:

• To synthesize and screen libraries of novel urea-based compounds.
• To identify potent inhibitors of serine hydrolases, particularly FAAH.
• To explore structure-activity relationships for further drug development.

Main Methods:

• Preparation of two distinct urea compound libraries: one with electron-deficient acyl anilines and another with acyl pyrazoles.
• Utilizing these libraries for fragment-based screening.
• Elaboration of promising pyrazole-based scaffolds.

Main Results:

• Successful synthesis of two novel urea libraries.
• Identification of a subset of compounds suitable for fragment screening and structural diversification.
• Discovery of highly potent irreversible inhibitors of fatty acid amide hydrolase (FAAH) derived from pyrazole-based ureas, with apparent Ki values in the picomolar range.
• These pyrazole-based inhibitors are complementary to previously reported aniline-based inhibitors.

Conclusions:

• Novel urea scaffolds can be effectively employed for serine hydrolase inhibition.
• Pyrazole-based ureas represent a promising chemotype for developing potent FAAH inhibitors.
• The identified inhibitors offer a foundation for further optimization and therapeutic applications targeting FAAH-related conditions.