Benzodiazepinone Derivatives as CRTH2 Antagonists

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Drug Discovery

Background:

• Chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) antagonists are under investigation for asthma and COPD.
• Lead optimization of CRTH2 antagonists revealed an intramolecular hydrogen bond in ortho-phenylsulfonamido benzophenone derivatives.

Purpose of the Study:

• To design and synthesize novel, conformationally constrained benzodiazepinones as potent CRTH2 antagonists.
• To investigate the structure-activity relationship (SAR) of these constrained compounds.
• To elucidate potential bound conformations to CRTH2 for pharmacophore modeling.

Main Methods:

• Synthesis of conformationally constrained benzodiazepinones.
• Evaluation of antagonist potency using binding assays.
• Assessment of functional activity in human eosinophil shape change assays.
• Conformational analysis of benzodiazepinones and benzophenones.

Main Results:

• Benzodiazepinones demonstrated significantly higher potency (2 orders of magnitude) compared to flexible bisaryl ethers in binding assays.
• Selected benzodiazepinones, including compound 6, exhibited potent activity in the human eosinophil shape change assay.
• Conformational analysis provided insights into SAR and suggested potential CRTH2-bound conformations.

Conclusions:

• Conformationally constrained benzodiazepinones represent a promising class of potent CRTH2 antagonists.
• The rigid structures offer a better understanding of CRTH2 antagonist SAR.
• These findings can inform the development of pharmacophore models for CRTH2 antagonists.