794535-36-7Relevant articles and documents
Discovery of a potent and selective prostaglandin D2 receptor antagonist, [(3R)-4-(4-chlorobenzyl)-7-fluoro-5-(methylsulfonyl)-1,2,3,4- tetrahydrocyclopenta[b]indol-3-yl]-acetic acid (MK-0524)
Sturino, Claudio F.,O'Neill, Gary,Lachance, Nicolas,Boyd, Michael,Berthelette, Carl,Labelle, Marc,Li, Lianhai,Roy, Bruno,Scheigetz, John,Tsou, Nancy,Aubin, Yves,Bateman, Kevin P.,Chauret, Nathalie,Day, Stephen H.,Lévesque, Jean-Fran?ois,Seto, Carmai,Silva, Jose H.,Trimble, Laird A.,Carriere, Marie-Claude,Denis, Danielle,Greig, Gillian,Kargman, Stacia,Lamontagne, Sonia,Mathieu, Marie-Claude,Sawyer, Nicole,Slipetz, Deborah,Abraham, William M.,Jones, Tom,McAuliffe, Malia,Piechuta, Hana,Nicoll-Griffith, Deborah A.,Wang, Zhaoyin,Zamboni, Robert,Young, Robert N.,Metters, Kathleen M.
, p. 794 - 806 (2007/10/03)
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 μM for 6 and 3900 μM for 7). This pharmacokinetic liability was circumvented by replacing the 7-methylsulfone substituent present in 6 and 7 with a fluorine atom resulting in antagonists with diminished propensity for biliary excretion and with superior pharmacokinetic profiles. Further optimization led to the discovery of the potent and selective DP antagonist 13.
