title: The Discovery of in Vivo Active Mitochondrial Branched-Chain Aminotransferase (BCATm) Inhibitors by Hybridizing Fragment and HTS Hits.
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.
authors.affiliation: GlaxoSmithKline R&D, Medicines Research Centre , Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.|Department of Pure and Applied Chemistry, University of Strathclyde , 295 Cathedral Street, Glasgow, G1 1XL, U.K.
authors.forename: Sophie M
authors.initials: SM
authors.lastname: Bertrand
authors.affiliation: Centre de Recherche, GlaxoSmithKline R&D, Les Ulis , 25, 27 Avenue du Québec, 91140 Villebon sur Yvette, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Ancellin
authors.affiliation: Centre de Recherche, GlaxoSmithKline R&D, Les Ulis , 25, 27 Avenue du Québec, 91140 Villebon sur Yvette, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Beaufils
authors.affiliation: GlaxoSmithKline R&D, Medicines Research Centre , Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Bingham
authors.affiliation: GlaxoSmithKline R&D, Medicines Research Centre , Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.|Department of Pure and Applied Chemistry, University of Strathclyde , 295 Cathedral Street, Glasgow, G1 1XL, U.K.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Borthwick
authors.affiliation: Centre de Recherche, GlaxoSmithKline R&D, Les Ulis , 25, 27 Avenue du Québec, 91140 Villebon sur Yvette, France.
authors.forename: Anne-Bénédicte
authors.initials: AB
authors.lastname: Boullay
authors.affiliation: Centre de Recherche, GlaxoSmithKline R&D, Les Ulis , 25, 27 Avenue du Québec, 91140 Villebon sur Yvette, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Boursier
authors.affiliation: GlaxoSmithKline R&D, Medicines Research Centre , Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Carter
authors.affiliation: GlaxoSmithKline R&D, Medicines Research Centre , Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
authors.forename: Chun-wa
authors.initials: CW
authors.lastname: Chung
authors.affiliation: GlaxoSmithKline R&D, Medicines Research Centre , Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
authors.forename: Ian
authors.initials: I
authors.lastname: Churcher
authors.affiliation: Centre de Recherche, GlaxoSmithKline R&D, Les Ulis , 25, 27 Avenue du Québec, 91140 Villebon sur Yvette, France.
authors.forename: Nerina
authors.initials: N
authors.lastname: Dodic
authors.affiliation: Centre de Recherche, GlaxoSmithKline R&D, Les Ulis , 25, 27 Avenue du Québec, 91140 Villebon sur Yvette, France.
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Fouchet
authors.affiliation: GlaxoSmithKline R&D, Medicines Research Centre , Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
authors.forename: Charlène
authors.initials: C
authors.lastname: Fournier
authors.affiliation: GlaxoSmithKline R&D, Medicines Research Centre , Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
authors.forename: Peter L
authors.initials: PL
authors.lastname: Francis
authors.affiliation: GlaxoSmithKline R&D, Medicines Research Centre , Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Gummer
authors.affiliation: Centre de Recherche, GlaxoSmithKline R&D, Les Ulis , 25, 27 Avenue du Québec, 91140 Villebon sur Yvette, France.
authors.forename: Kenny
authors.initials: K
authors.lastname: Herry
authors.affiliation: GlaxoSmithKline R&D, Medicines Research Centre , Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
authors.forename: Andrew
authors.initials: A
authors.lastname: Hobbs
authors.affiliation: GlaxoSmithKline R&D, Medicines Research Centre , Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
authors.forename: Clare I
authors.initials: CI
authors.lastname: Hobbs
authors.affiliation: GlaxoSmithKline R&D, Medicines Research Centre , Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
authors.forename: Paul
authors.initials: P
authors.lastname: Homes
authors.affiliation: Department of Pure and Applied Chemistry, University of Strathclyde , 295 Cathedral Street, Glasgow, G1 1XL, U.K.
authors.forename: Craig
authors.initials: C
authors.lastname: Jamieson
authors.affiliation: Centre de Recherche, GlaxoSmithKline R&D, Les Ulis , 25, 27 Avenue du Québec, 91140 Villebon sur Yvette, France.
authors.forename: Edwige
authors.initials: E
authors.lastname: Nicodeme
authors.affiliation: GlaxoSmithKline R&D, Medicines Research Centre , Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Pickett
authors.affiliation: GlaxoSmithKline R&D, Medicines Research Centre , Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
authors.forename: Iain H
authors.initials: IH
authors.lastname: Reid
authors.affiliation: GlaxoSmithKline R&D, Medicines Research Centre , Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
authors.forename: Graham L
authors.initials: GL
authors.lastname: Simpson
authors.affiliation: GlaxoSmithKline R&D, Medicines Research Centre , Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Sloan
authors.affiliation: GlaxoSmithKline R&D, Medicines Research Centre , Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Smith
authors.affiliation: GlaxoSmithKline R&D, Medicines Research Centre , Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
authors.forename: Donald O'N
authors.initials: DO
authors.lastname: Somers
authors.affiliation: GlaxoSmithKline R&D, Medicines Research Centre , Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
authors.forename: Claus
authors.initials: C
authors.lastname: Spitzfaden
authors.affiliation: Department of Pure and Applied Chemistry, University of Strathclyde , 295 Cathedral Street, Glasgow, G1 1XL, U.K.
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Suckling
authors.affiliation: GlaxoSmithKline R&D, Medicines Research Centre , Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
authors.forename: Klara
authors.initials: K
authors.lastname: Valko
authors.affiliation: GlaxoSmithKline R&D, Medicines Research Centre , Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Washio
authors.affiliation: GlaxoSmithKline R&D, Medicines Research Centre , Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Young
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000201:enzymology; D000818:Animals; D018360:Crystallography, X-Ray; D006801:Humans; D007532:Isoleucine / Q000097:blood; D007930:Leucine / Q000097:blood; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D000637:Transaminases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D014633:Valine / Q000097:blood
chemical_list: C000603791:2-((4-chloro-2,6-difluorobenzyl)amino)-7-oxo-5-propyl-4,7-dihydropyrazolo(1,5-a)pyrimidine-3-carbonitrile; D024101:Mitochondrial Proteins; D011720:Pyrazoles; D011744:Pyrimidinones; D007532:Isoleucine; C490590:BCAT1 protein, human; C094227:Bcat1 protein, mouse; D000637:Transaminases; D007930:Leucine; D014633:Valine