Non-prostanoid thromboxane A2 receptor antagonists with a dibenzoxepin ring system. 1

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Cardiovascular Research

Background:

• Thromboxane A2 (TXA2) and Prostaglandin H2 (PGH2) receptors play critical roles in platelet aggregation and cardiovascular function.
• Developing selective antagonists for these receptors is a key strategy for treating thrombotic disorders.

Purpose of the Study:

• To synthesize novel 11-[[2-[(arylsulfonyl)amino]ethyl]thio]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acids and related derivatives.
• To evaluate the TXA2/PGH2 receptor antagonizing activity of these compounds.
• To investigate structure-activity relationships and identify potent drug candidates.

Main Methods:

• Synthesis of a series of dibenzoxepin and dibenzthiepin derivatives.
• In vitro receptor binding assays to determine inhibition constants (K(i)) for TXA2/PGH2 receptors.
• Ex vivo assessment of U-46619-induced guinea pig platelet aggregation.
• Chiral resolution and comparative activity assessment of enantiomers.

Main Results:

• Compounds (+/-)-11-[[2-[(Styrylsulfonyl)amino]ethyl]-thio]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid (41) and (+/-)-11-[[2-[(phenylsulfonyl)amino]ethyl]thio]-6,11-dihydrodibenz[b,e]thiepin-2-carboxylic acid (4af) exhibited high affinity (K(i) 6.5 and 3.7 nM, respectively).
• Both compounds significantly inhibited platelet aggregation ex vivo at 10 mg/kg.
• The (-)-isomer of compound 41 was 60-fold more potent than the (+)-isomer in receptor binding.
• Some synthesized compounds demonstrated dual TXA2/PGH2 receptor antagonism and TXA2 synthase inhibition.

Conclusions:

• Novel dibenzoxepin and dibenzthiepin derivatives are potent TXA2/PGH2 receptor antagonists.
• Stereochemistry is crucial for activity, with the (-)-isomer of compound 41 being highly potent.
• These compounds represent promising leads for the development of antiplatelet and antithrombotic agents.