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The Discovery of in Vivo Active Mitochondrial Branched-Chain Aminotransferase (BCATm) Inhibitors by Hybridizing Fragment and HTS Hits

2015; American Chemical Society; Volume: 58; Issue: 18 Linguagem: Inglês

10.1021/acs.jmedchem.5b00313

1520-4804

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

HIV/AIDS drug development and treatment

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.