Preparation of phenylephrine 3-O-sulfate as the major in vivo metabolite of phenylephrine to facilitate its pharmacokinetic and metabolism studies.

INTRODUCTION: The in vivo disposition and metabolism of phenylephrine have not been establishedby previous analytical methods and there is a lack of available standards for quantitating the metabolites. METHODS: We pursued and compared the preparation of sulfation metabolites of phenylephrine and its ethyl analog etilefrine via chemical and bio-synthesis. RESULTS: Both sulfates were obtained in higher yield and purity through chemical syntheses compared to biosynthesis. DISCUSSION: A facile method for the production of phenylephrine 3-O-sulfate and etilefrine 3-O-sulfate was established. These compounds will be useful in the development of analytical assays for studying the pharmacokinetics of phenylephrine and its main route of metabolism in the presence of formulation changes and pharmacogenetic variation.

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).

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.