Claudio F Sturino, Gary O'Neill, Nicolas Lachance, Michael Boyd, Carl Berthelette, Marc Labelle, Lianhai Li, Bruno Roy, John Scheigetz, Nancy Tsou, Yves Aubin, Kevin P Bateman, Nathalie Chauret, Stephen H Day, Jean-François Lévesque, Carmai Seto, Jose H Silva, Laird A Trimble, Marie-Claude Carriere, Danielle Denis, Gillian Greig, Stacia Kargman, Sonia Lamontagne, Marie-Claude Mathieu, Nicole Sawyer, Deborah Slipetz, William M Abraham, Tom Jones, Malia McAuliffe, Hana Piechuta, Deborah A Nicoll-Griffith, Zhaoyin Wang, Robert Zamboni, Robert N Young, Kathleen M Metters
The discovery of the potent and selective prostaglandin D2 (PGD2) receptor (DP) antagonist [(3R)-4-(4-chlorobenzyl)-7-fluoro-5-(methylsulfonyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]-acetic acid (13) is presented. Initial lead antagonists 6 and 7 were found to be potent and selective DP antagonists (DP Ki = 2.0 nM for each); however, they both suffered from poor pharmacokinetic profiles, short half-lives and high clearance rates in rats. Rat bile duct cannulation studies revealed that high concentrations of parent drug were present in the biliary fluid (Cmax = 1100 microM for 6 and 3900 microM for 7)...
February 22, 2007: Journal of Medicinal Chemistry