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]-acetic Acid (MK-0524)

Abstract

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). 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.

Pharmacological Characterization of MK-7246, a Potent and Selective CRTH2 (Chemoattractant Receptor-Homologous Molecule Expressed on T-Helper Type 2 Cells) Antagonist

“…Inhibition of forskolin-induced increase in intracellular cAMP using HEK-human CRTH2 cells was evaluated as described elsewhere (Sawyer et al, 2002). Functional cell-based assays to measure activity on DP1 (inhibition of PGD 2 -induced increases in cAMP in platelets) and the prostanoid receptor TP (inhibition of thromboxane-induced platelet aggregation) were performed as described elsewhere (Sturino et al, 2007).…”

International Union of Basic and Clinical Pharmacology. LXXXIII: Classification of Prostanoid Receptors, Updating 15 Years of Progress

“…3), the acetate unit is located on C4; its binding pK i for the human rc-DP 1 receptor is 7.7 (Torisu et al, 2004). In the Merck series of DP 1 antagonists, the positions of the carboxylic group and the substituents on the benzene ring of the indole template were optimized to yield MK-0524 (laropiprant) (Sturino et al, 2007). Laropiprant has very high affinity for the human rc-DP 1 receptor (pK i , 10.5); it also has ϳ300-fold lower affinity for the corresponding TP receptor, which requires consideration when using it to characterize prostanoid receptors.…”

Flushing Profile of Extended-Release Niacin/Laropiprant at Initiation of Therapy in Asian Lipid Clinic Patients

“…The PGD 2 -mediated flushing pathway is independent of the mechanism underlying the beneficial lipid-modifying effects of niacin [16], allowing for the development of an agent that inhibits PGD 2 -mediated flushing while maintaining the lipid-modifying efficacy of niacin. Laropiprant (LRPT) is a potent, once-daily, highly selective PGD 2 receptor 1 antagonist that has been shown to reduce the incidence and intensity of niacin-induced flushing [17]. LRPT has been combined with extended-release (ER) niacin (ERN; Merck & Co. Inc.) into a fixed-dose combination tablet (ERN/LRPT), administered via a simplified dosing regimen: 1 g/20 mg for 4 weeks followed by 2 g/40 mg for maintenance therapy.…”