| Literature DB >> 26090771 |
Sophie M Bertrand1,2, Nicolas Ancellin3, Benjamin Beaufils3, Ryan P Bingham1, Jennifer A Borthwick1,2, Anne-Bénédicte Boullay3, Eric Boursier3, Paul S Carter1, Chun-wa Chung1, Ian Churcher1, Nerina Dodic3, Marie-Hélène Fouchet3, Charlène Fournier1, Peter L Francis1, Laura A Gummer1, Kenny Herry3, Andrew Hobbs1, Clare I Hobbs1, Paul Homes1, Craig Jamieson2, Edwige Nicodeme3, Stephen D Pickett1, Iain H Reid1, Graham L Simpson1, Lisa A Sloan1, Sarah E Smith1, Donald O'N Somers1, Claus Spitzfaden1, Colin J Suckling2, Klara Valko1, Yoshiaki Washio1, Robert J Young1.
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.Entities:
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Year: 2015 PMID： 26090771 DOI： 10.1021/acs.jmedchem.5b00313
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446