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

Bertrand, Sophie M. and Ancellin, Nicolas and Beaufils, Benjamin and Bingham, Ryan P. and Borthwick, Jennifer A. and Boullay, Anne Bénédicte and Boursier, Eric and Carter, Paul S. and Chung, Chun Wa and Churcher, Ian and Dodic, Nerina and Fouchet, Marie Hélène and Fournier, Charlène and Francis, Peter L. and Gummer, Laura A. and Herry, Kenny and Hobbs, Andrew and Hobbs, Clare I. and Homes, Paul and Jamieson, Craig and Nicodeme, Edwige and Pickett, Stephen D. and Reid, Iain H. and Simpson, Graham L. and Sloan, Lisa A. and Smith, Sarah E. and Somers, Donald O N and Spitzfaden, Claus and Suckling, Colin J. and Valko, Klara and Washio, Yoshiaki and Young, Robert 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). pp. 7140-7163. ISSN 0022-2623 (

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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.


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