Harnessing biosynthesis and quantitative NMR for late stage functionalization of lead molecules: Application to the M1 positive allosteric modulator (PAM) program

Bioorg Med Chem Lett. 2018 Jun 15;28(11):2068-2073. doi: 10.1016/j.bmcl.2018.04.054. Epub 2018 Apr 23.

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.

Keywords: Biosynthesis; Late-stage diversification; M1 positive allosteric modulator (PAM) program; Medicinal chemistry design cycle.

MeSH terms

  • Bridged Bicyclo Compounds / chemistry
  • Bridged Bicyclo Compounds / metabolism*
  • Cyclohexanes / chemistry
  • Cyclohexanes / metabolism*
  • Dose-Response Relationship, Drug
  • Heterocyclic Compounds / chemistry
  • Heterocyclic Compounds / metabolism*
  • Magnetic Resonance Spectroscopy
  • Microsomes, Liver / chemistry
  • Microsomes, Liver / metabolism
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Bridged Bicyclo Compounds
  • Cyclohexanes
  • Heterocyclic Compounds
  • Cyclohexane