Fengjiun Kuo

Although fenofibrate (1a) is commercially available and clinically effective in lowering serum triglycerides, its activity and sub‐type selectivity at the PPARα receptors are only moderate; therefore, there exists a need for more potent and sub‐type selective PPARα agonists. To that end, discovery efforts have identified 2‐methyl‐2‐(4‐[3‐[1‐(4‐methylbenzyl)‐5‐oxo‐4,5‐dihydro‐1H‐[1,2,4]triazol‐3‐yl]propyl]phenoxy)propionic acid (2), a potent and selective human PPARα receptor agonist. In support of pre‐clinical ADME studies and bioanalysis, three isotopomers of 2 have been synthesized. The results of these efforts are described below. Copyright © 2007 John Wiley & Sons, Ltd.

Carbon‐14‐labeled 6‐(4‐methanesulfonylphenyl)‐5‐[4‐(2‐piperidin‐1‐yl‐ethoxy)phenoxy]naphthalen‐2‐ol, a novel selective estrogen receptor modulator (SERM) was synthesized. The key component, 6‐methoxy‐1‐tetralone‐[carbonyl‐¹⁴C], was synthesized from 3‐(3‐methoxyphenyl)‐propionic acid via an intra‐molecular Friedel–Crafts acylation of 4‐(3‐methoxyphenyl)butanoic acid‐[carboxy‐¹⁴C]. A palladium catalyzed alpha‐keto arylation of 6‐methoxy‐1‐tetralone with 4‐methanesulfonyl‐phenyl bromide, followed by a sequence of bromination, DDQ dehydrogenation, aryl Ullmann reaction, and demethylation with BBr₃ gave the desired product LY2066948‐[¹⁴C]. Copyright © 2007 John Wiley & Sons, Ltd.

Human Factor Xa is a trypsin‐like serine protease, which serves a critical role in blood coagulation events. LY517717 is currently under clinical investigation as a Factor Xa inhibitor. To support the ADME studies, LY517717 was synthesized usingD‐phenylglycine with a carbon‐14 labeled carboxyl moiety. This key component,D‐phenylglycine‐[carboxyl‐¹⁴C], was synthesized by a Strecker synthesis on benzaldehyde with potassium [¹⁴C]cyanide, followed by a resolution ofDL‐phenyl‐glycine methyl ester‐[carbonyl‐¹⁴C] with (+)‐tartaric acid in the presence of benzaldehyde. Copyright © 2004 John Wiley & Sons, Ltd.

A process for double deuterium labeling of an alcohol was developed. The process was utilized in the subsequent tritium labeling of a secondary alcohol with high specific activity (24 Ci/mmol) by reduction of the corresponding ketone using sodium borotritide. The starting ketone was first brominated with pyridinium tribromide; the resulting alpha bromoketone was then reduced in THF/alcohol in the presence of Ni(OAc)₂. The alcohol was then converted to 2‐amino‐4‐fluorobicyclo[3.1.0]hexane‐2,6‐dicarboxylic acid‐[³H₂], an mGluR agonist. Copyright © 2004 John Wiley & Sons, Ltd.