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

Basic Information

ID: ALA3616381

Journal: J Med Chem

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

Authors: Bertrand SM, Ancellin N, Beaufils B, Bingham RP, Borthwick JA, Boullay AB, Boursier E, Carter PS, Chung CW, Churcher I, Dodic N, Fouchet MH, Fournier C, Francis PL, Gummer LA, Herry K, Hobbs A, Hobbs CI, Homes P, Jamieson C, Nicodeme E, Pickett SD, Reid IH, Simpson GL, Sloan LA, Smith SE, Somers DO, Spitzfaden C, Suckling CJ, Valko K, Washio Y, Young RJ.

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.

CiteXplore: 26090771

DOI: 10.1021/acs.jmedchem.5b00313

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