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Synthesis of the tritiated isotopomers of enzastaurin and its N ‐ des ‐pyridylmethyl metabolite for use in ADME studies
Author(s) -
Wheeler William J.,
Clodfelter Dean K.
Publication year - 2008
Publication title -
journal of labelled compounds and radiopharmaceuticals
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.432
H-Index - 47
eISSN - 1099-1344
pISSN - 0362-4803
DOI - 10.1002/jlcr.1497
Subject(s) - chemistry , isotopomers , tritium , metabolite , in vivo , metabolism , adme , pyrrole , chemical synthesis , in vitro , stereochemistry , biochemistry , organic chemistry , physics , microbiology and biotechnology , molecule , nuclear physics , biology
Enzastaurin (3‐(1‐methyl‐1 H ‐indol‐3‐yl)‐4‐[1‐[1‐(2‐pyridinylmethyl)‐4‐piperidinyl]‐1 H ‐indol‐3‐yl]‐1 H ‐pyrrole‐2,5‐dione, 1), an agent with potential utility in the treatment of solid tumors, is currently in phase II clinical trials. Enzastaurin undergoes metabolism in vitro and in vivo to several products of oxidative metabolism, the major one of which is 3‐(1‐methyl‐1 H ‐indol‐3‐yl)‐4‐(1‐piperidin‐4‐yl‐1 H ‐indol‐3‐yl)‐1 H ‐pyrrole‐2,5‐dione (2). In a model study, the attempted synthesis 1‐[ 2 H] by reaction of 1 with deuterium gas in the presence of Ir[(COD)(Cy 3 P)pyr]PF 6 (Crabtree's catalyst) was unsuccessful. Alternatively, it was decided to prepare tritiated 2 as both a final product and the starting material for the tritiation of 1. We have reported herein a route that was developed for use in the preparation of tritium‐labeled 2‐[ 3 H] and its successful conversion to 1‐[ 3 H]. Copyright © 2008 John Wiley & Sons, Ltd.