Minor structural modifications convert the dual TP/CRTH2 antagonist ramatroban into a highly selective and potent CRTH2 antagonist.
Ramatroban, a thromboxane A(2) receptor (TP) antagonist with clinical efficacy in asthma and allergic rhinitis, was recently shown to also antagonize the prostaglandin D(2) 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.
Ulven
Trond
T
7TM Pharma A/S, Fremtidsvej 3, DK-2970 Hørsholm, Denmark. tu@7tm.com
Kostenis
Evi
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D018926:Anti-Allergic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019390:Arrestins / Q000378:metabolism; D001667:Binding, Competitive; D002227:Carbazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004735:Energy Transfer; D007295:Inositol Phosphates / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008163:Luminescent Measurements; D008968:Molecular Conformation; D021381:Protein Transport / Q000187:drug effects; D011869:Radioligand Assay; D011971:Receptors, Immunologic / Q000819:agonists / Q000037:antagonists & inhibitors*; D011982:Receptors, Prostaglandin / Q000819:agonists / Q000037:antagonists & inhibitors*; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000071557:beta-Arrestins
D018926:Anti-Allergic Agents; D019390:Arrestins; D002227:Carbazoles; D007295:Inositol Phosphates; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013449:Sulfonamides; D000071557:beta-Arrestins; D000242:Cyclic AMP; C063119:ramatroban; C036293:prostaglandin D2 receptor