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)

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 DenisGillian 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

Research output: Contribution to journalArticlepeer-review

162 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)794-806
Number of pages13
JournalJournal of Medicinal Chemistry
Issue number4
StatePublished - Feb 22 2007
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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