Identification of an indole series of prostaglandin D2 receptor antagonists

• Published in: Bioorganic & medicinal chemistry letters Vol. 16; no. 11; pp. 3043 - 3048
• Main Authors: STURINO, Claudio F, LACHANCE, Nicolas, CAUCHON, Elizabeth, CARRIERE, Marie-Claude, DENIS, Danielle, GREIG, Gillian, KARGMAN, Stacia, LAMONTAGNE, Sonia, MATHIEU, Marie-Claude, SAWYER, Nicole, SLIPETZ, Deborah, O'NEILL, Gary, BOYD, Michael, ZHAOYIN WANG, ZAMBONI, Robert, METTERS, Kathleen M, YOUNG, Robert N, BERTHELETTE, Carl, LABELLE, Marc, LIANHAI LI, ROY, Bruno, SCHEIGETZ, John, TSOU, Nancy, BRIDEAU, Christine
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier 01-06-2006
• Subjects: Biological and medical sciences; Histamine and antagonists. Allergy; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacology; Medical sciences; Molecular Structure; Pharmacology. Drug treatments; Receptors, Immunologic - antagonists & inhibitors; Receptors, Immunologic - metabolism; Receptors, Prostaglandin - antagonists & inhibitors; Receptors, Prostaglandin - metabolism; Safrole - analogs & derivatives; Safrole - chemistry; Structure-Activity Relationship; PGD2; Purine nucleotide; DP receptor antagonist; Arachidonic acid derivatives; Prostaglandin G2; DP prostanoid receptor; Indole; Cyclic AMP; Polyunsaturated fatty acid; Selectivity; Prostaglandin D2; In vitro; Optimization; Blood plasma; Platelet; Structure activity relation; Production; Antagonist; Inhibition; Indole derivatives; Chemical synthesis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2006.02.062

A novel indole series of PGD2 receptor (DP receptor) antagonists is presented. Optimization of this series led to the identification of potent and selective DP receptor antagonists. In particular, antagonists 35 and 36 were identified with Ki values of 2.6 and 1.8 nM, respectively. These two antagonists are also potent in a DP functional assay where they inhibit the PGD2 induced cAMP production in platelet rich plasma with IC50 values of 7.9 and 8.6 nM, respectively. The structure-activity relationships of this indole series of DP receptor antagonists will also be discussed.