Potent multitarget FAAH-COX inhibitors: Design and structure-activity relationship studies

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Drug Discovery

Background:

• Non-steroidal anti-inflammatory drugs (NSAIDs) target cyclooxygenase (COX)-1 and COX-2 enzymes for pain and inflammation but cause gastrointestinal damage.
• Blocking fatty acid amide hydrolase (FAAH) alongside COX enhances NSAID efficacy and reduces gastrointestinal injury by increasing protective endocannabinoids like anandamide.

Purpose of the Study:

• To rationally design and characterize the first class of potent, multitargeting FAAH-COX inhibitors.
• To explore structure-activity relationships (SAR) for novel analgesic and anti-inflammatory agents with improved safety profiles.

Main Methods:

• Rational drug design and synthesis of novel chemical entities targeting both FAAH and COX.
• Structure-activity relationship (SAR) studies focused on a prototype inhibitor (10r, ARN2508).
• Pharmacological evaluation, including absolute configurational assignment and in vivo activity assessment of single enantiomers.

Main Results:

• Identification of achiral (18b) and racemic (29a-c, 29e) analogs through SAR exploration.
• The single enantiomer (S)-(+)-10r was identified as the first highly potent and selective chiral inhibitor of FAAH-COX.
• Demonstration of marked in vivo activity for (S)-(+)-10r.

Conclusions:

• Simultaneous inhibition of FAAH and COX represents a promising therapeutic strategy for pain and inflammation.
• (S)-(+)-10r is a lead compound for developing novel analgesics and anti-inflammatory drugs with potentially reduced side effects.