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

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.