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

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

  • J Med Chem. 2015 Sep 24;58(18):7140-63. doi: 10.1021/acs.jmedchem.5b00313.
Sophie M Bertrand 1 2,  Nicolas Ancellin 3,  Benjamin Beaufils 3,  Ryan P Bingham 1,  Jennifer A Borthwick 1 2,  Anne-Bénédicte Boullay 3,  Eric Boursier 3,  Paul S Carter 1,  Chun-wa Chung 1,  Ian Churcher 1,  Nerina Dodic 3,  Marie-Hélène Fouchet 3,  Charlène Fournier 1,  Peter L Francis 1,  Laura A Gummer 1,  Kenny Herry 3,  Andrew Hobbs 1,  Clare I Hobbs 1,  Paul Homes 1,  Craig Jamieson 2,  Edwige Nicodeme 3,  Stephen D Pickett 1,  Iain H Reid 1,  Graham L Simpson 1,  Lisa A Sloan 1,  Sarah E Smith 1,  Donald O'N Somers 1,  Claus Spitzfaden 1,  Colin J Suckling 2,  Klara Valko 1,  Yoshiaki Washio 1,  Robert J Young 1
Affiliations

Affiliations

  • 1 GlaxoSmithKline R&D, Medicines Research Centre , Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
  • 2 Department of Pure and Applied Chemistry, University of Strathclyde , 295 Cathedral Street, Glasgow, G1 1XL, U.K.
  • 3 Centre de Recherche, GlaxoSmithKline R&D, Les Ulis , 25, 27 Avenue du Québec, 91140 Villebon sur Yvette, France.
PMID: 26090771 DOI: 10.1021/acs.jmedchem.5b00313
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.

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