3-Indolyl sultams as selective CRTh2 antagonists.
L Nathan Tumey1, Michael J Robarge, Elizabeth Gleason
1Athersys, Inc., 3201 Carnegie Ave., Cleveland, OH 44115, USA. tumeyn@wyeth.com
Bioorganic & Medicinal Chemistry Letters
|May 12, 2010
Summary
Researchers discovered new CRTh2 antagonists, 3-indolyl sultams, that show low nM affinity for the prostaglandin D(2) receptor. These compounds are selective, offering potential for treating conditions like asthma by targeting eosinophil and basophil recruitment.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Immunology
Background:
- The chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTh2) is a key prostaglandin D(2) receptor involved in allergic inflammation.
- CRTh2 mediates the recruitment of eosinophils and basophils, crucial inflammatory cells in the pathogenesis of asthma.
- Targeting CRTh2 presents a potential therapeutic strategy for managing asthmatic conditions.
Purpose of the Study:
- To discover and characterize novel antagonists of the CRTh2 receptor.
- To evaluate the affinity and selectivity of newly synthesized compounds for CRTh2.
- To explore the potential of these antagonists in the context of CRTh2-mediated inflammatory responses.
Main Methods:
- Synthesis of a novel series of 3-indolyl sultam compounds.
- In vitro assessment of receptor binding affinity for CRTh2.
- Evaluation of compound selectivity against related prostaglandin receptors, specifically DP1 and thromboxane A(2) receptor (TP).
Main Results:
- Discovery of a novel series of 3-indolyl sultam antagonists.
- These compounds exhibit low nanomolar (nM) affinity for the CRTh2 receptor.
- Demonstrated high selectivity for CRTh2 over DP1 and TP receptors.
Conclusions:
- The novel 3-indolyl sultams are potent and selective CRTh2 antagonists.
- These findings support the development of CRTh2 antagonists as a therapeutic approach for asthma and other allergic diseases.
- Further investigation into the in vivo efficacy of these compounds is warranted.
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