The discovery of in vivo active mitochondrial branched-chain aminotransferase (BCATm) inhibitors by hybridizing fragment and HTS hits

Sophie M. Bertrand, Nicolas Ancellin, Benjamin Beaufils, Ryan P. Bingham, Jennifer A. Borthwick, Anne Bénédicte Boullay, Eric Boursier, Paul S. Carter, Chun Wa Chung, Ian Churcher, Nerina Dodic, Marie Hélène Fouchet, Charlène Fournier, Peter L. Francis, Laura A. Gummer, Kenny Herry, Andrew Hobbs, Clare I. Hobbs, Paul Homes, Craig JamiesonEdwige Nicodeme, Stephen D. Pickett, Iain H. Reid, Graham L. Simpson, Lisa A. Sloan, Sarah E. Smith, Donald O N Somers, Claus Spitzfaden, Colin J. Suckling, Klara Valko, Yoshiaki Washio, Robert J. Young

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

The hybridization of hits, identified by complementary fragment and high throughput screens, enabled the discovery of the first series of potent inhibitors of mitochondrial branched-chain aminotransferase (BCATm) based on a 2-benzylamino-pyrazolo[1,5-a]pyrimidinone-3-carbonitrile template. Structure-guided growth enabled rapid optimization of potency with maintenance of ligand efficiency, while the focus on physicochemical properties delivered compounds with excellent pharmacokinetic exposure that enabled a proof of concept experiment in mice. Oral administration of 2-((4-chloro-2,6-difluorobenzyl)amino)-7-oxo-5-propyl-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carbonitrile 61 significantly raised the circulating levels of the branched-chain amino acids leucine, isoleucine, and valine in this acute study.

Original languageEnglish
Pages (from-to)7140-7163
Number of pages24
JournalJournal of Medicinal Chemistry
Volume58
Issue number18
Early online date19 Jun 2015
DOIs
Publication statusPublished - 24 Sep 2015

Keywords

  • branched-chain aminotransferases
  • BCATs
  • enzymes
  • amino acids

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    Bertrand, S. M., Ancellin, N., Beaufils, B., Bingham, R. P., Borthwick, J. A., Boullay, A. B., ... Young, R. J. (2015). The discovery of in vivo active mitochondrial branched-chain aminotransferase (BCATm) inhibitors by hybridizing fragment and HTS hits. Journal of Medicinal Chemistry, 58(18), 7140-7163. https://doi.org/10.1021/acs.jmedchem.5b00313