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

Journal of Medicinal Chemistry

Volumn 58, Issue 18, 2015, Pages 7140-7163

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

^a GLAXOSMITHKLINE   (United Kingdom)

^b GLAXOSMITHKLINE   (France)

^c UNIVERSITY OF STRATHCLYDE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

2 [(4 CHLORO 2,6 DIFLUOROBENZYL)AMINO] 7 OXO 5 PROPYL 4,7 DIHYDROPYRAZOLO[1,5 A]PYRIDIMINE 3 CARBONITRILE; AMINOTRANSFERASE INHIBITOR; ISOLEUCINE; LEUCINE; UNCLASSIFIED DRUG; VALINE; 2-((4-CHLORO-2,6-DIFLUOROBENZYL)AMINO)-7-OXO-5-PROPYL-4,7-DIHYDROPYRAZOLO(1,5-A)PYRIMIDINE-3-CARBONITRILE; AMINOTRANSFERASE; BCAT1 PROTEIN, HUMAN; BCAT1 PROTEIN, MOUSE; MITOCHONDRIAL PROTEIN; PYRAZOLE DERIVATIVE; PYRIMIDINONE DERIVATIVE;

ANIMAL EXPERIMENT; ARTICLE; CONTROLLED STUDY; DRUG BIOAVAILABILITY; DRUG POTENCY; DRUG SCREENING; DRUG SYNTHESIS; HYBRIDIZATION; IN VIVO STUDY; MALE; MOUSE; NONHUMAN; STRUCTURE ACTIVITY RELATION; ADIPOCYTE; ANIMAL; ANTAGONISTS AND INHIBITORS; BAGG ALBINO MOUSE; BLOOD; C57BL MOUSE; CHEMICAL STRUCTURE; CHEMISTRY; DRUG EFFECTS; ENZYMOLOGY; HUMAN; SYNTHESIS; X RAY CRYSTALLOGRAPHY;

ADIPOCYTES; ANIMALS; CRYSTALLOGRAPHY, X-RAY; HUMANS; ISOLEUCINE; LEUCINE; MICE, INBRED BALB C; MICE, INBRED C57BL; MITOCHONDRIAL PROTEINS; MODELS, MOLECULAR; PYRAZOLES; PYRIMIDINONES; STRUCTURE-ACTIVITY RELATIONSHIP; TRANSAMINASES; VALINE;

EID: 84942271775     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/acs.jmedchem.5b00313     Document Type: Article

References (62)

1. Hutson, S. Structure and function of branched chain aminotransferases Prog. Nucleic Acid Res. Mol. Biol. 2001, 70, 175-206
2. Hall, T. R.; Wallin, R.; Reinhart, G. D.; Hutson, S. M. Branched chain aminotransferase isoenzymes. Purification and characterization of the rat brain isoenzyme J. Biol. Chem. 1993, 268, 3092-3098
3. Harper, A. E. Thoughts on the role of branched-chain alpha-keto acid dehydrogenase complex in nitrogen metabolism Ann. N. Y. Acad. Sci. 1989, 573, 267-273
4. Hutson, S. M.; Wallin, R.; Hall, T. R. Identification of mitochondrial branched chain aminotransferase and its isoforms in rat tissues J. Biol. Chem. 1992, 267, 15681-15686
5. Hutson, S. M.; Fenstermacher, D.; Mahar, C. Role of mitochondrial transamination in branched chain amino acid metabolism J. Biol. Chem. 1988, 263, 3618-3625
6. Halton, T. L.; Hu, F. B. The effects of high protein diets on thermogenesis, satiety and weight loss: a critical review J. Am. Coll. Nutr. 2004, 23, 373-385
7. Layman, D. K.; Walker, D. A. Potential importance of leucine in treatment of obesity and the metabolic syndrome J. Nutr. 2006, 136, 319S-323S
8. She, P.; Reid, T. M.; Bronson, S. K.; Vary, T. C.; Hajnal, A.; Lynch, C. J.; Hutson, S. M. Disruption of BCATm in mice leads to increased energy expenditure associated with the activation of a futile protein turnover cycle Cell Metab. 2007, 6, 181-194
9. She, P.; Zhou, Y.; Zhang, Z.; Griffin, K.; Gowda, K.; Lynch, C. J. Disruption of BCAA metabolism in mice impairs exercise metabolism and endurance J. Appl. Physiol. 2010, 108, 941-949
10. Goto, M.; Miyahara, I.; Hirotsu, K.; Conway, M.; Yennawar, N.; Islam, M. M.; Hutson, S. M. Structural determinants for branched-chain aminotransferase isozyme-specific inhibition by the anticonvulsant drug gabapentin J. Biol. Chem. 2005, 280, 37246-37256
11. Hu, L. Y.; Boxer, P. A.; Kesten, S. R.; Lei, H. J.; Wustrow, D. J.; Moreland, D. W.; Zhang, L.; Ahn, K.; Ryder, T. R.; Liu, X.; Rubin, J. R.; Fahnoe, K.; Carroll, R. T.; Dutta, S.; Fahnoe, D. C.; Probert, A. W.; Roof, R. L.; Rafferty, M. F.; Kostlan, C. R.; Scholten, J. D.; Hood, M.; Ren, X. D.; Schielke, G. P.; Su, T. Z.; Taylor, C. P.; Mistry, A.; McConnell, P.; Hasemann, C.; Ohren, J. The design and synthesis of human branched-chain amino acid aminotransferase inhibitors for treatment of neurodegenerative diseases Bioorg. Med. Chem. Lett. 2006, 16, 2337-2340
12. Hutson, S. M.; Berkich, D.; Drown, P.; Xu, B.; Aschner, M.; LaNoue, K. F. Role of branched-chain aminotransferase isoenzymes and gabapentin in neurotransmitter metabolism J. Neurochem. 1998, 71, 863-874
13. Mendoza, R.; Petros, A. M.; Liu, Y.; Thimmapaya, R.; Surowy, C. S.; Leise, W. F.; Pereda-Lopez, A.; Panchal, S. C.; Sun, C. Cracking the molecular weight barrier: fragment screening of an aminotransferase using an NMR-based functional assay Bioorg. Med. Chem. Lett. 2011, 21, 5248-5250
14. Valko, K.; Bevan, C.; Reynolds, D. Chromatographic Hydrophobicity Index by Fast-Gradient RP-HPLC: A High-Throughput Alternative to Log P/log D Anal. Chem. 1997, 69, 2022-2029
15. Bhattachar, S. N.; Wesley, J. A.; Seadeek, C. Evaluation of the chemiluminescent nitrogen detector for solubility determinations to support drug discovery J. Pharm. Biomed. Anal. 2006, 41, 152-157
16. Carr, R. A. E.; Congreve, M.; Murray, C. W.; Rees, D. C. Fragment-based lead discovery: leads by design Drug Discovery Today 2005, 10, 987-992
17. Congreve, M.; Murray, C. W.; Carr, R.; Rees, D. C. Fragment-based lead discovery Annu. Rep. Med. Chem. 2007, 42, 431-448
18. Joseph-McCarthy, D.; Campbell, A. J.; Kern, G.; Moustakas, D. Fragment-Based Lead Discovery and Design J. Chem. Inf. Model. 2014, 54, 693-704
19. Murray, C. W.; Rees, D. C. The rise of fragment-based drug discovery Nature Chem. 2009, 1, 187-192
20. Chessari, G.; Woodhead, A. J. From fragment to clinical candidate-a historical perspective Drug Discovery Today 2009, 14, 668-675
21. Murray, C. W.; Verdonk, M. L.; Rees, D. C. Experiences in fragment-based drug discovery Trends Pharmacol. Sci. 2012, 33, 224-232
22. Gleeson, M. P. Generation of a Set of Simple, Interpretable ADMET Rules of Thumb J. Med. Chem. 2008, 51, 817-834
23. Hughes, J. D.; Blagg, J.; Price, D. A.; Bailey, S.; DeCrescenzo, G. A.; Devraj, R. V.; Ellsworth, E.; Fobian, Y. M.; Gibbs, M. E.; Gilles, R. W.; Greene, N.; Huang, E.; Krieger-Burke, T.; Loesel, J.; Wager, T.; Whiteley, L.; Zhang, Y. Physiochemical drug properties associated with in vivo toxicological outcomes Bioorg. Med. Chem. Lett. 2008, 18, 4872-4875
24. Leeson, P. D.; Springthorpe, B. The influence of drug-like concepts on decision-making in medicinal chemistry Nature Rev. Drug Discovery 2007, 6, 881-890
25. Leeson, P. D.; Empfield, J. R. Reducing the risk of drug attrition associated with physicochemical properties Annu. Rep. Med. Chem. 2010, 45, 393-407
26. Price, D. A.; Blagg, J.; Jones, L.; Greene, N.; Wager, T. Physicochemical drug properties associated with in vivo toxicological outcomes: a review Expert Opin. Drug Metab. Toxicol. 2009, 5, 921-931
27. Waring, M. J. Lipophilicity in drug discovery Expert Opin. Drug Discovery 2010, 5, 235-248
28. Hill, A. P.; Young, R. J. Getting physical in drug discovery: a contemporary perspective on solubility and hydrophobicity Drug Discovery Today 2010, 15, 648-655
29. Young, R. J.; Green, D. V. S.; Luscombe, C. N.; Hill, A. P. Getting physical in drug discovery II: the impact of chromatographic hydrophobicity measurements and aromaticity Drug Discovery Today 2011, 16, 822-830
30. Ritchie, T. J.; MacDonald, S. J. F. The impact of aromatic ring count on compound developability: are too many aromatic rings a liability in drug design? Drug Discovery Today 2009, 14, 1011-1020
31. Ritchie, T. J.; MacDonald, S. J. F.; Young, R. J.; Pickett, S. D. The impact of aromatic ring count on compound developability: further insights by examining carbo- and hetero-aromatic and -aliphatic ring types Drug Discovery Today 2011, 16, 164-171
32. Hopkins, A. L.; Keserue, G. M.; Leeson, P. D.; Rees, D. C.; Reynolds, C. H. The role of ligand efficiency metrics in drug discovery Nature Rev. Drug Discovery 2014, 13, 105-121
33. Young, R. J. Physical Properties in Drug Design. In Topics in Medicinal Chemistry; Springer: Berlin Heidelberg, 2014.
34. Shultz, M. D. Setting expectations in molecular optimizations: strengths and limitations of commonly used composite parameters Bioorg. Med. Chem. Lett. 2013, 23, 5980-5991
35. Hopkins, A. L.; Groom, C. R.; Alex, A. Ligand efficiency: a useful metric for lead selection Drug Discovery Today 2004, 9, 430-431
36. Kuntz, I. D.; Chen, K.; Sharp, K. A.; Kollman, P. A. The maximal affinity of ligands Proc. Natl. Acad. Sci. U. S. A. 1999, 96, 9997-10002
37. Mortenson, P. N.; Murray, C. W. Assessing the lipophilicity of fragments and early hits J. Comput.-Aided Mol. Des. 2011, 25, 663-667
38. Borthwick, J. A.; Ancellin, N.; Bertrand, S. M.; Bingham, R. P.; Carter, P. S.; Chung, C.-W.; Churcher, I.; Dodic, N.; Fournier, C.; Francis, P. L.; Hobbs, A.; Jamieson, C.; Pickett, S. D.; Smith, S.; Somers, D. ON.; Spitzfaden, C.; Young, R. J. Structurally Diverse Mitochondrial Branched Chain Aminotransferase (BCATm) Leads With Varying Binding Modes Identified by Fragment Screening. J. Med. Chem. 2015.
39. Legon, A. C.; Millen, D. J. Angular geometries and other properties of hydrogen-bonded dimers: a simple electrostatic interpretation of the success of the electron-pair model Chem. Soc. Rev. 1987, 16, 467-498
40. Mukaiyama, H.; Nishimura, T.; Shiohara, H.; Kobayashi, S.; Komatsu, Y.; Kikuchi, S.; Tsuji, E.; Kamada, N.; Ohnota, H.; Kusama, H. Discovery of novel 2-anilinopyrazolo[1,5-a]pyrimidine derivatives as c-Src kinase inhibitors for the treatment of acute ischemic stroke Chem. Pharm. Bull. 2007, 55, 881-889
41. Brooks, D. W.; Lu, L. D. L.; Masamune, S. C-Acylation under virtually neutral conditions Angew. Chem., Int. Ed. Engl. 1979, 18, 72-74
42. Denton, R. M.; An, J.; Adeniran, B.; Blake, A. J.; Lewis, W.; Poulton, A. M. Catalytic Phosphorus(V)-Mediated Nucleophilic Substitution Reactions: Development of a Catalytic Appel Reaction J. Org. Chem. 2011, 76, 6749-6767
43. Appel, R. Tertiary phosphane/tetrachloromethane, a versatile reagent for chlorination, dehydration, and phosphorus-nitrogen linking Angew. Chem. 1975, 87, 863-874
44. Brown, E. V. Willgerodt reaction Synthesis 1975, 358-375
45. Moghaddam, F. M.; Ghaffarzadeh, M. Microwave-assisted rapid hydrolysis and preparation of thioamides by Willgerodt-Kindler reaction Synth. Commun. 2001, 31, 317-321
46. Tominaga, Y.; Matsuoka, Y.; Kohra, S.; Hosomi, A. A novel preparation of polarized ethylenes by the reaction of thioamides or dithiocarboxylates with tetracyanoethylene oxide. Synthesis of pyrazoles and pyrimidines Heterocycles 1987, 26, 613-616
47. Tominaga, Y.; Matsuoka, Y.; Oniyama, Y.; Uchimura, Y.; Komiya, H.; Hirayama, M.; Kohra, S.; Hosomi, A. Polarized ethylenes. IV. Synthesis of polarized ethylene using thioamides and methyl dithiocarboxylates and their application to syntheses of pyrazoles, pyrimidines, pyrazolo[3,4-d]pyrimidines and 5-aza[2.2.3]cyclazines J. Heterocycl. Chem. 1990, 27, 647-660
48. Goodford, P. J. A computational procedure for determining energetically favorable binding sites on biologically important macromolecules J. Med. Chem. 1985, 28, 849-857
49. Carosati, E.; Sciabola, S.; Cruciani, G. Hydrogen Bonding Interactions of Covalently Bonded Fluorine Atoms: From Crystallographic Data to a New Angular Function in the GRID Force Field J. Med. Chem. 2004, 47, 5114-5125
50. Taylor, E. C.; Hartke, K. S. The Reaction of Malononitrile with Substituted Hydrazines: New Routes to 4-Aminopyrazolo[3,4-d]pyrimidines1,2 J. Am. Chem. Soc. 1959, 81, 2456-2464
51. Howard, J. A. K.; Hoy, V. J.; OHagan, D.; Smith, G. T. How good is fluorine as a hydrogen bond acceptor? Tetrahedron 1996, 52, 12613-12622
52. Berecz, G.; Reiter, J.; Csaszar, J. On triazoles. Part 40. Non-catalytic dehalogenation of some 5-chloro-1,2,4-triazolo[1,5-a]pyrimidine derivatives J. Heterocycl. Chem. 1999, 36, 1199-1212
53. Tominaga, Y.; Honkawa, Y.; Hara, M.; Hosomi, A. Synthesis of pyrazolo[3,4-d]pyrimidine derivatives using ketene dithioacetals J. Heterocycl. Chem. 1990, 27, 775-783
54. Friesner, R. A.; Murphy, R. B.; Repasky, M. P.; Frye, L. L.; Greenwood, J. R.; Halgren, T. A.; Sanschagrin, P. C.; Mainz, D. T. Extra Precision Glide: Docking and Scoring Incorporating a Model of Hydrophobic Enclosure for Protein-Ligand Complexes J. Med. Chem. 2006, 49, 6177-6196
55. Halgren, T. A.; Murphy, R. B.; Friesner, R. A.; Beard, H. S.; Frye, L. L.; Pollard, W. T.; Banks, J. L. Glide: A new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening J. Med. Chem. 2004, 47, 1750-1759
56. Friesner, R. A.; Banks, J. L.; Murphy, R. B.; Halgren, T. A.; Klicic, J. J.; Mainz, D. T.; Repasky, M. P.; Knoll, E. H.; Shelley, M.; Perry, J. K.; Shaw, D. E.; Francis, P.; Shenkin, P. S. Glide: A new approach for rapid, accurate docking and scoring. 1. method and assessment of docking accuracy J. Med. Chem. 2004, 47, 1739-1749
57. Otwinowski, Z.; Minor, W. Processing of X-ray diffraction data collected in oscillation mode Methods Enzymol. 1997, 276, 307-326
58. Leslie, A. G. W.; Powell, H. R. Evolving Methods for Macromolecular Crystallography; Springer Press: New York, 2007; pp 41-51.
59. Evans, P. Scaling and assessment of data quality Acta Crystallogr., Sect. D: Biol. Crystallogr. 2006, D62, 72-82
60. Bailey, S. The CCP4 suite: programs for protein crystallography Acta Crystallogr., Sect. D: Biol. Crystallogr. 1994, D50, 760-763
61. Murshudov, G. N.; Vagin, A. A.; Dodson, E. J. Refinement of macromolecular structures by the maximum-likelihood method Acta Crystallogr., Sect. D: Biol. Crystallogr. 1997, D53, 240-255
62. Emsley, P.; Cowtan, K. Coot: model-building tools for molecular graphics Acta Crystallogr., Sect. D: Biol. Crystallogr. 2004, D60, 2126-2132