[2-(O-Phenylalkyl)phenoxy]alkylamines III: Synthesis and selective serotonin-2 receptor binding (2)

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Cardiovascular Research

Background:

• Serotonin-2 (5-HT2) and dopamine-2 (D2) receptor ligands are investigated.
• Compound 17, a phenylethylphenoxy]ethylpyrrolidine derivative, exhibits high 5-HT2 receptor affinity and potent inhibition of platelet aggregation.
• Compound 17 causes gastric irritation in rats, necessitating further development.

Purpose of the Study:

• To synthesize and evaluate novel phenylethylphenoxy]ethylpyrrolidine derivatives as potential antithrombotic agents.
• To develop a safer and more effective alternative to compound 17.
• To assess the antithrombotic and antiplatelet efficacy of compound R-102444.

Main Methods:

• Synthesis of 12-(2-phenylethyl)phenoxy]ethylpyrrolidine derivatives.
• In vitro receptor binding assays for 5-HT2 and D2 receptors.
• Ex vivo assessment of 5-HT-induced platelet aggregation in rats.
• Evaluation of gastric irritation in rats.
• In vivo antithrombotic activity in a rat photochemically-induced thrombosis model.

Main Results:

• Compound 17 demonstrated high 5-HT2 receptor affinity and potent inhibition of platelet aggregation.
• Compound 17 induced gastric irritation in rats.
• Compound R-102444, a prodrug of compound 17, showed marked inhibition of platelet aggregation without gastric irritation.
• R-102444 exhibited superior antiplatelet and antithrombotic effects compared to sarpogrelate and its metabolite M-1.
• R-102444 demonstrated more potent antithrombotic effects than sarpogrelate in vivo.

Conclusions:

• Compound R-102444 is a promising antithrombotic agent with improved safety and efficacy.
• R-102444 represents a significant advancement over existing agents like sarpogrelate.
• Further investigation of R-102444 for clinical application is warranted.