Tetrahydroindolizinone NK1 antagonists

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Neuroscience

Background:

• Neurokinin-1 (NK1) receptor antagonists are investigated for therapeutic potential.
• Previous lead structures based on 5,5-fused pyrrolidines showed moderate activity.
• Development of novel scaffolds is crucial for improved NK1 receptor antagonism.

Purpose of the Study:

• To identify and characterize a new class of potent NK1 receptor antagonists.
• To explore structure-activity relationships (SAR) of tetrahydroindolizinone derivatives.
• To evaluate the in vivo efficacy and safety profiles of promising compounds.

Main Methods:

• Synthesis of a novel series of tetrahydroindolizinone compounds.
• In vitro assessment of NK1 receptor binding affinity and functional activity.
• In vivo evaluation using a gerbil foot tapping model for NK1 receptor occupancy.
• Assessment of P450 inhibition and human pregnane X receptor (hPXR) induction.

Main Results:

• A new series of tetrahydroindolizinone compounds with potent NK1 receptor antagonist activity was identified.
• These compounds exhibited improved functional activities compared to 5,5-fused pyrrolidine analogs.
• Detailed SAR at the 7-position of the tetrahydroindolizinone core was established.
• Several compounds demonstrated high NK1 receptor occupancy in vivo.
• Compound 40 showed high binding affinity, good selectivity, favorable in vivo properties, and clean safety profiles.

Conclusions:

• The tetrahydroindolizinone core represents a promising scaffold for developing potent NK1 receptor antagonists.
• Compound 40 is a lead candidate with excellent pharmacological and safety characteristics.
• This new class of antagonists holds potential for treating NK1 receptor-mediated conditions.