Discovery of a Potent and Selective Prostaglandin D2 Receptor Antagonist, [(3R)-4-(4-Chloro- benzyl)-7-fluoro-5-(methylsulfonyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]-ace
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- 作者：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 ; Ste
- 刊名：Journal of Medicinal Chemistry
- 出版年：2007
- 出版时间：February 22, 2007
- 年：2007
- 卷：50
- 期：4
- 页码：794 - 806
- 全文大小：164K
- 年卷期：v.50,no.4(February 22, 2007)
- ISSN：1520-4804
文摘
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) ispresented. 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 andhigh clearance rates in rats. Rat bile duct cannulation studies revealed that high concentrations of parentdrug were present in the biliary fluid (Cmax = 1100 
M for 6 and 3900 M for 7). This pharmacokineticliability was circumvented by replacing the 7-methylsulfone substituent present in 6 and 7 with a fluorineatom resulting in antagonists with diminished propensity for biliary excretion and with superiorpharmacokinetic profiles. Further optimization led to the discovery of the potent and selective DP antagonist13.
M for 6 and 3900 M for 7). This pharmacokineticliability was circumvented by replacing the 7-methylsulfone substituent present in 6 and 7 with a fluorineatom resulting in antagonists with diminished propensity for biliary excretion and with superiorpharmacokinetic profiles. Further optimization led to the discovery of the potent and selective DP antagonist13.