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.
MeSH terms
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Adipocytes / drug effects
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Adipocytes / enzymology
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Animals
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Crystallography, X-Ray
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Humans
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Isoleucine / blood
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Leucine / blood
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mitochondrial Proteins / antagonists & inhibitors*
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Models, Molecular
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Pyrazoles / chemical synthesis
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Pyrazoles / chemistry*
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Pyrazoles / pharmacology
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Pyrimidinones / chemical synthesis
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Pyrimidinones / chemistry*
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Pyrimidinones / pharmacology
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Structure-Activity Relationship
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Transaminases / antagonists & inhibitors*
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Transaminases / chemistry
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Valine / blood
Substances
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2-((4-chloro-2,6-difluorobenzyl)amino)-7-oxo-5-propyl-4,7-dihydropyrazolo(1,5-a)pyrimidine-3-carbonitrile
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Mitochondrial Proteins
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Pyrazoles
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Pyrimidinones
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Isoleucine
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BCAT1 protein, human
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Bcat1 protein, mouse
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Transaminases
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Leucine
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Valine
Associated data
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PDB/5BWR
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PDB/5BWT
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PDB/5BWU
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PDB/5BWV
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PDB/5BWW
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PDB/5BWX