Minor Structural Modifications Convert the Dual TP/CRTH2 Antagonist Ramatroban into a Highly Selective and Potent CRTH2 Antagonist

• Published in: Journal of medicinal chemistry Vol. 48; no. 4; pp. 897 - 900
• Main Authors: Ulven, Trond, Kostenis, Evi
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 24.02.2005; Amer Chemical Soc
• Subjects: Anti-Allergic Agents - chemical synthesis; Anti-Allergic Agents - chemistry; Anti-Allergic Agents - pharmacology; Arrestins - metabolism; beta-Arrestins; Binding, Competitive; Biological and medical sciences; Carbazoles - chemical synthesis; Carbazoles - chemistry; Carbazoles - pharmacology; Chemistry, Medicinal; Cyclic AMP - antagonists & inhibitors; Cyclic AMP - biosynthesis; Energy Transfer; Inositol Phosphates - antagonists & inhibitors; Inositol Phosphates - biosynthesis; Life Sciences & Biomedicine; Luminescent Measurements; Medical sciences; Molecular Conformation; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Protein Transport - drug effects; Radioligand Assay; Receptors, Immunologic - agonists; Receptors, Immunologic - antagonists & inhibitors; Receptors, Prostaglandin - agonists; Receptors, Prostaglandin - antagonists & inhibitors; Receptors, Thromboxane A2, Prostaglandin H2 - antagonists & inhibitors; Respiratory system; Science & Technology; Structure-Activity Relationship; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Sulfonamides - pharmacology; MIGRATION; ACTIVATION; PHARMACOKINETICS; INFLAMMATION; EOSINOPHILS; BAY U3405; ASTHMA; TH2 CELLS CRTH2; PROSTAGLANDIN D-2; RECEPTOR ANTAGONIST; T cell receptor; Sulfonamide; Nitrogen heterocycle; Selectivity; Prostaglandin D2; Tricyclic compound; In vitro; α-Aminoacid; Structure activity relation; Chemoattractant receptor homologous molecule expressed on th2; Affinity; Aromatic compound; Th2 lymphocyte; Fluorine Organic compounds; Antagonist; Chemical synthesis; Biological receptor
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm049036i

Ramatroban, a thromboxane A2 receptor (TP) antagonist with clinical efficacy in asthma and allergic rhinitis, was recently shown to also antagonize the prostaglandin D2 receptor CRTH2. Here we report that minor structural changes to ramatroban result in a compound (13) with complete lack of activity on TP but sub-nanomolar potency toward CRTH2. This is the first selective CRTH2 antagonist described to date, and should prove highly valuable in further elucidating the biological significance of CRTH2.