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Harnessing biosynthesis and quantitative NMR for late stage functionalization of lead molecules: Application to the
Michael A Brodney1, Raman Sharma2, John T Lazzaro2
1Pfizer Worldwide Research and Development, 610 Main Street, Cambridge, MA 02139, United States.
Abstract:
A facile method for late stage diversification of lead molecules for the M1 PAM program using biosynthesis is described. Liver microsomes from several species are screened to identify a high turnover system. Subsequent incubations using less than 1 mg of substrate generate nanomole quantities of drug metabolites that are purified, characterized by microcryoprobe NMR spectroscopy, and quantified to known concentrations to enable rapid biology testing. The late-stage diversification of lead compounds provides rapid SAR feedback to the medicinal chemistry design cycle.
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