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 & 12 others 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

Research output: Contribution to journalArticle

16 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 languageEnglish
Pages (from-to)7140-7163
Number of pages24
JournalJournal of Medicinal Chemistry
Volume58
Issue number18
Early online date19 Jun 2015
DOIs
Publication statusPublished - 24 Sep 2015

Fingerprint

Pyrimidinones
Branched Chain Amino Acids
Pharmacokinetics
Isoleucine
Valine
Leucine
Oral Administration
Maintenance
Throughput
Ligands
Growth
Experiments
2-((4-chloro-2,6-difluorobenzyl)amino)-7-oxo-5-propyl-4,7-dihydropyrazolo(1,5-a)pyrimidine-3-carbonitrile
branched-chain-amino-acid transaminase

Keywords

  • branched-chain aminotransferases
  • BCATs
  • enzymes
  • amino acids

Cite this

Bertrand, S. M., Ancellin, N., Beaufils, B., Bingham, R. P., Borthwick, J. A., Boullay, A. B., ... 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
Bertrand, Sophie M. ; Ancellin, Nicolas ; Beaufils, Benjamin ; Bingham, Ryan P. ; Borthwick, Jennifer A. ; Boullay, Anne Bénédicte ; Boursier, Eric ; Carter, Paul S. ; Chung, Chun Wa ; Churcher, Ian ; Dodic, Nerina ; Fouchet, Marie Hélène ; Fournier, Charlène ; Francis, Peter L. ; Gummer, Laura A. ; Herry, Kenny ; Hobbs, Andrew ; Hobbs, Clare I. ; Homes, Paul ; Jamieson, Craig ; Nicodeme, Edwige ; Pickett, Stephen D. ; Reid, Iain H. ; Simpson, Graham L. ; Sloan, Lisa A. ; Smith, Sarah E. ; Somers, Donald O N ; Spitzfaden, Claus ; Suckling, Colin J. ; Valko, Klara ; Washio, Yoshiaki ; Young, Robert J. / The discovery of in vivo active mitochondrial branched-chain aminotransferase (BCATm) inhibitors by hybridizing fragment and HTS hits. In: Journal of Medicinal Chemistry. 2015 ; Vol. 58, No. 18. pp. 7140-7163.
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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

The discovery of in vivo active mitochondrial branched-chain aminotransferase (BCATm) inhibitors by hybridizing fragment and HTS hits. / Bertrand, Sophie M.; Ancellin, Nicolas; Beaufils, Benjamin; Bingham, Ryan P.; Borthwick, Jennifer A.; Boullay, Anne Bénédicte; Boursier, Eric; Carter, Paul S.; Chung, Chun Wa; Churcher, Ian; Dodic, Nerina; Fouchet, Marie Hélène; Fournier, Charlène; Francis, Peter L.; Gummer, Laura A.; Herry, Kenny; Hobbs, Andrew; Hobbs, Clare I.; Homes, Paul; Jamieson, Craig; Nicodeme, Edwige; Pickett, Stephen D.; Reid, Iain H.; Simpson, Graham L.; Sloan, Lisa A.; Smith, Sarah E.; Somers, Donald O N; Spitzfaden, Claus; Suckling, Colin J.; Valko, Klara; Washio, Yoshiaki; Young, Robert J.

In: Journal of Medicinal Chemistry, Vol. 58, No. 18, 24.09.2015, p. 7140-7163.

Research output: Contribution to journalArticle

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

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KW - branched-chain aminotransferases

KW - BCATs

KW - enzymes

KW - amino acids

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DO - 10.1021/acs.jmedchem.5b00313

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SP - 7140

EP - 7163

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

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