The discovery of in vivo active mitochondrial branched-chain aminotransferase (BCATm) inhibitors by hybridizing fragment and HTS hits

Sophie M. Bertrand; Nicolas Ancellin; Benjamin Beaufils; Ryan P. Bingham; Jennifer A. Borthwick; Anne Bénédicte Boullay; Eric Boursier; Paul S. Carter; Chun Wa Chung; Ian Churcher; Nerina Dodic; Marie Hélène Fouchet; Charlène Fournier; Peter L. Francis; Laura A. Gummer; Kenny Herry; Andrew Hobbs; Clare I. Hobbs; Paul Homes; Craig Jamieson; Edwige Nicodeme; Stephen D. Pickett; Iain H. Reid; Graham L. Simpson; Lisa A. Sloan; Sarah E. Smith; Donald O N Somers; Claus Spitzfaden; Colin J. Suckling; Klara Valko; Yoshiaki Washio; Robert J. Young

doi:10.1021/acs.jmedchem.5b00313

The discovery of in vivo active mitochondrial branched-chain aminotransferase (BCATm) inhibitors by hybridizing fragment and HTS hits

Sophie M. Bertrand^*, Nicolas Ancellin, Benjamin Beaufils, Ryan P. Bingham, Jennifer A. Borthwick, Anne Bénédicte Boullay, Eric Boursier, Paul S. Carter, Chun Wa Chung, Ian Churcher, Nerina Dodic, Marie Hélène Fouchet, Charlène Fournier, Peter L. Francis, Laura A. Gummer, Kenny Herry, Andrew Hobbs, Clare I. Hobbs, Paul Homes, Craig JamiesonEdwige Nicodeme, Stephen D. Pickett, Iain H. Reid, Graham L. Simpson, Lisa A. Sloan, Sarah E. Smith, Donald O N Somers, Claus Spitzfaden, Colin J. Suckling, Klara Valko, Yoshiaki Washio, Robert J. Young

^*Corresponding author for this work

Pure And Applied Chemistry

Research output: Contribution to journal › Article › peer-review

37 Citations (Scopus)

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.

Original language	English
Pages (from-to)	7140-7163
Number of pages	24
Journal	Journal of Medicinal Chemistry
Volume	58
Issue number	18
Early online date	19 Jun 2015
DOIs	https://doi.org/10.1021/acs.jmedchem.5b00313
Publication status	Published - 24 Sept 2015

Keywords

branched-chain aminotransferases
BCATs
enzymes
amino acids

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10.1021/acs.jmedchem.5b00313

Cite this

Bertrand, S. M., Ancellin, N., Beaufils, B., Bingham, R. P., Borthwick, J. A., Boullay, A. B., Boursier, E., Carter, P. S., Chung, C. W., Churcher, I., Dodic, N., Fouchet, M. H., Fournier, C., Francis, P. L., Gummer, L. A., Herry, K., Hobbs, A., Hobbs, C. I., Homes, P., ... Young, R. J. (2015). The discovery of in vivo active mitochondrial branched-chain aminotransferase (BCATm) inhibitors by hybridizing fragment and HTS hits. Journal of Medicinal Chemistry, 58(18), 7140-7163. https://doi.org/10.1021/acs.jmedchem.5b00313

@article{ce640cd1fc864fc5b2033778b0f38041,

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.",

keywords = "branched-chain aminotransferases, BCATs, enzymes, amino acids",

author = "Bertrand, \{Sophie M.\} and Nicolas Ancellin and Benjamin Beaufils and Bingham, \{Ryan P.\} and Borthwick, \{Jennifer A.\} and Boullay, \{Anne B{\'e}n{\'e}dicte\} and Eric Boursier and Carter, \{Paul S.\} and Chung, \{Chun Wa\} and Ian Churcher and Nerina Dodic and Fouchet, \{Marie H{\'e}l{\`e}ne\} and Charl{\`e}ne Fournier and Francis, \{Peter L.\} and Gummer, \{Laura A.\} and Kenny Herry and Andrew Hobbs and Hobbs, \{Clare I.\} and Paul Homes and Craig Jamieson and Edwige Nicodeme and Pickett, \{Stephen D.\} and Reid, \{Iain H.\} and Simpson, \{Graham L.\} and Sloan, \{Lisa A.\} and Smith, \{Sarah E.\} and Somers, \{Donald O N\} and Claus Spitzfaden and Suckling, \{Colin J.\} and Klara Valko and Yoshiaki Washio and Young, \{Robert J.\}",

year = "2015",

month = sep,

day = "24",

doi = "10.1021/acs.jmedchem.5b00313",

language = "English",

volume = "58",

pages = "7140--7163",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "18",

}

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, DON, Spitzfaden, C, Suckling, CJ, Valko, K, Washio, Y & Young, RJ 2015, 'The discovery of in vivo active mitochondrial branched-chain aminotransferase (BCATm) inhibitors by hybridizing fragment and HTS hits', Journal of Medicinal Chemistry, vol. 58, no. 18, pp. 7140-7163. https://doi.org/10.1021/acs.jmedchem.5b00313

TY - JOUR

T1 - The discovery of in vivo active mitochondrial branched-chain aminotransferase (BCATm) inhibitors by hybridizing fragment and HTS hits

AU - Bertrand, Sophie M.

AU - Ancellin, Nicolas

AU - Beaufils, Benjamin

AU - Bingham, Ryan P.

AU - Borthwick, Jennifer A.

AU - Boullay, Anne Bénédicte

AU - Boursier, Eric

AU - Carter, Paul S.

AU - Chung, Chun Wa

AU - Churcher, Ian

AU - Dodic, Nerina

AU - Fouchet, Marie Hélène

AU - Fournier, Charlène

AU - Francis, Peter L.

AU - Gummer, Laura A.

AU - Herry, Kenny

AU - Hobbs, Andrew

AU - Hobbs, Clare I.

AU - Homes, Paul

AU - Jamieson, Craig

AU - Nicodeme, Edwige

AU - Pickett, Stephen D.

AU - Reid, Iain H.

AU - Simpson, Graham L.

AU - Sloan, Lisa A.

AU - Smith, Sarah E.

AU - Somers, Donald O N

AU - Spitzfaden, Claus

AU - Suckling, Colin J.

AU - Valko, Klara

AU - Washio, Yoshiaki

AU - Young, Robert J.

PY - 2015/9/24

Y1 - 2015/9/24

N2 - 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.

AB - 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.

KW - branched-chain aminotransferases

KW - BCATs

KW - enzymes

KW - amino acids

UR - http://www.scopus.com/inward/record.url?scp=84942271775&partnerID=8YFLogxK

U2 - 10.1021/acs.jmedchem.5b00313

DO - 10.1021/acs.jmedchem.5b00313

M3 - Article

AN - SCOPUS:84942271775

SN - 0022-2623

VL - 58

SP - 7140

EP - 7163

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 18

ER -

The discovery of in vivo active mitochondrial branched-chain aminotransferase (BCATm) inhibitors by hybridizing fragment and HTS hits

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Craig Jamieson

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The discovery of in vivo active mitochondrial branched-chain aminotransferase (BCATm) inhibitors by hybridizing fragment and HTS hits

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Craig Jamieson

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