Targeting the prostaglandin D2 receptors DP and CRTH2 for treatment of inflammation.
The involvement of prostaglandin D(2) (PGD(2)) in inflammatory diseases like allergy and asthma is well established, thus blocking the effect of this mediator represents a novel therapeutic approach for the treatment of such diseases. PGD(2) is now known to act through two seven-transmembrane (7TM) receptors, DP (DP(1)) and CRTH2 (DP(2)), which are also activated by several endogenous metabolites from the arachidonic acid cascade, making the regulatory system highly complex. There has recently been a considerable effort aimed at developing antagonists of the PGD(2) receptors for treatment of inflammatory conditions like asthma and rhinitis. Several potent DP antagonists are now known, and one of these is currently in clinical trials for treatment of asthma. CRTH2 has received much attention since its identification as the second high affinity PGD(2) receptor in 2001, and a number of potent and selective antagonists have recently become available. This review will briefly discuss the biological background and validation of DP and CRTH2 as targets for antiinflammatory drugs, and then highlight developments in medicinal chemistry which have appeared in journals and patent applications in the last few years, and which have brought us closer to therapeutic applications of PGD(2) receptor antagonists in various indications.
Ulven
Trond
T
Department of Chemistry, University of Southern Denmark, Campusvej 55, DK-5230 Odense M, Denmark. ulven@chem.sdu.dk
Kostenis
Evi
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D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D015195:Drug Design; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000276:immunology; D015394:Molecular Structure; D015230:Prostaglandin D2 / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000276:immunology; D011982:Receptors, Prostaglandin / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000276:immunology; D013329:Structure-Activity Relationship; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology
D000893:Anti-Inflammatory Agents; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D015230:Prostaglandin D2; C036293:prostaglandin D2 receptor