(Z)-2-Cyano-3-hydroxy-but-2-enoic acid (4-trifluoromethyl-phenyl)-amide

ID: ALA973

Max Phase: Approved

First Approval: 2012

Molecular Formula: C12H9F3N2O2

Molecular Weight: 270.21

Molecule Type: Small molecule

Names and Identifiers

Synonyms: Teriflunomide | A77 1726 | HMR-1726 | HMR1726

Trade Names(2): Aubagio | Teriflunomide mylan

Canonical SMILES:  C/C(O)=C(\C#N)C(=O)Nc1ccc(C(F)(F)F)cc1

Standard InChI:  InChI=1S/C12H9F3N2O2/c1-7(18)10(6-16)11(19)17-9-4-2-8(3-5-9)12(13,14)15/h2-5,18H,1H3,(H,17,19)/b10-7-

Standard InChI Key:  UTNUDOFZCWSZMS-YFHOEESVSA-N

Molfile:  

     RDKit          2D

 19 19  0  0  0  0  0  0  0  0999 V2000
    0.0000    1.6477    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    1.4283    0.0000    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    2.1443    2.8834    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
    0.7155    2.8845    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
    5.9259    2.5096    0.0000 F   0  0  0  0  0  0  0  0  0  0  0  0
    5.7107    4.1284    0.0000 F   0  0  0  0  0  0  0  0  0  0  0  0
    6.4298    2.8936    0.0000 F   0  0  0  0  0  0  0  0  0  0  0  0
    1.4289    0.8249    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    4.2873    1.6445    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    5.0037    2.0578    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    4.2855    3.2974    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    3.5737    2.8846    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    2.8578    1.6454    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    0.7148    2.0596    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    2.1437    2.0585    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    1.4289    1.6465    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    5.0008    2.8882    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    3.5725    2.0573    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    5.7138    3.3034    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
  1 14  1  0
  2  8  3  0
  3 15  2  0
  4 14  1  0
  5 19  1  0
  6 19  1  0
  7 19  1  0
  8 16  1  0
  9 10  2  0
  9 18  1  0
 10 17  1  0
 11 12  1  0
 11 17  2  0
 12 18  2  0
 13 15  1  0
 13 18  1  0
 14 16  2  0
 15 16  1  0
 17 19  1  0
M  END

Alternative Forms

1. Parent:

   

   ALA973

   TERIFLUNOMIDE

Molecule Features

Natural Product: No

Oral: Yes

Chemical Probe: No

Parenteral: No

Molecule Type: Small molecule

Topical: No

First In Class: Yes

Black Box: Yes

Chirality: Yes

Availability: Yes

Prodrug: No

Calculated Properties

Molecular Weight: 270.21

Molecular Weight (Monoisotopic): 270.0616

AlogP: 3.00

#Rotatable Bonds: 2

Polar Surface Area: 73.12

Molecular Species: ACID

HBA: 3

HBD: 2

#RO5 Violations: ┄

HBA (Lipinski): 4

HBD (Lipinski): 2

#RO5 Violations (Lipinski): ┄

CX Acidic pKa: 5.48

CX Basic pKa: ┄

CX LogP: 2.14

CX LogD: 0.23

Aromatic Rings: 1

Heavy Atoms: 19

QED Weighted: 0.49

Np Likeness Score: -1.35

References

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13. Unpublished dataset, 

14. USP Dictionary of USAN and International Names (2010 edition) and USAN registrations 2007-date, 

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22. Zhu J, Han L, Diao Y, Ren X, Xu M, Xu L, Li S, Li Q, Dong D, Huang J, Liu X, Zhao Z, Wang R, Zhu L, Xu Y, Qian X, Li H..  (2015)  Design, synthesis, X-ray crystallographic analysis, and biological evaluation of thiazole derivatives as potent and selective inhibitors of human dihydroorotate dehydrogenase.,  58  (3): [PMID:25580811] [10.1021/jm501127s]

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26. British National Formulary (72nd edition), 

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29. Unpublished dataset, 

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34. Boschi D, Pippione AC, Sainas S, Lolli ML..  (2019)  Dihydroorotate dehydrogenase inhibitors in anti-infective drug research.,  183  [PMID:31557612] [10.1016/j.ejmech.2019.111681]

35. Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani.  (2020)  Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen,  [10.6019/CHEMBL4495564]

36. Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani.  (2020)  Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen,  [10.6019/CHEMBL4495564]

37. Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani.  (2020)  Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen,  [10.6019/CHEMBL4495564]

38. Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen.  (2020)  Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort,  [10.6019/CHEMBL4495565]

39. Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen.  (2020)  Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort,  [10.6019/CHEMBL4495565]

40. Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen.  (2020)  Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort,  [10.6019/CHEMBL4495565]

41. Unpublished dataset, 

42. Kokkonda S, Deng X, White KL, El Mazouni F, White J, Shackleford DM, Katneni K, Chiu FCK, Barker H, McLaren J, Crighton E, Chen G, Angulo-Barturen I, Jimenez-Diaz MB, Ferrer S, Huertas-Valentin L, Martinez-Martinez MS, Lafuente-Monasterio MJ, Chittimalla R, Shahi SP, Wittlin S, Waterson D, Burrows JN, Matthews D, Tomchick D, Rathod PK, Palmer MJ, Charman SA, Phillips MA..  (2020)  Lead Optimization of a Pyrrole-Based Dihydroorotate Dehydrogenase Inhibitor Series for the Treatment of Malaria.,  63  (9): [PMID:32248693] [10.1021/acs.jmedchem.0c00311]

43. Ellen Van Damme.  (2021)  Screening of ~5500 FDA-approved drugs and clinical candidates for anti-SARS-CoV-2 activity,  [10.6019/CHEMBL4651402]

44. Serafini M,Cordero-Sanchez C,Di Paola R,Bhela IP,Aprile S,Purghè B,Fusco R,Cuzzocrea S,Genazzani AA,Riva B,Pirali T.  (2020)  Store-Operated Calcium Entry as a Therapeutic Target in Acute Pancreatitis: Discovery and Development of Drug-Like SOCE Inhibitors.,  63  (23): [PMID:33253576] [10.1021/acs.jmedchem.0c01305]

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46. Bernhard Ellinger, Justus Dick, Vanessa Lage-Rupprecht, Bruce Schultz, Andrea Zaliani, Marcin Namysl, Stephan Gebel, Ole Pless, Jeanette Reinshagen, Christian Ebeling, Alexander Esser, Marc Jacobs, Carsten Claussen, and Martin Hofmann-Apitius.  (2021)  HDAC6 screening dataset using tau-based substrate in an enzymatic assay yields selective inhibitors and activators,  [10.6019/CHEMBL4808148]

47. Luo X, Cai G, Guo Y, Gao C, Huang W, Zhang Z, Lu H, Liu K, Chen J, Xiong X, Lei J, Zhou X, Wang J, Liu Y..  (2021)  Exploring Marine-Derived Ascochlorins as Novel Human Dihydroorotate Dehydrogenase Inhibitors for Treatment of Triple-Negative Breast Cancer.,  64  (18.0): [PMID:34516133] [10.1021/acs.jmedchem.1c01402]

48. Chen JA, Ma H, Liu Z, Tian J, Lu S, Fang W, Ze S, Lu W, Xie Q, Huang J, Wang Y..  (2022)  Discovery of Orally Available Retinoic Acid Receptor-Related Orphan Receptor γ-t/Dihydroorotate Dehydrogenase Dual Inhibitors for the Treatment of Refractory Inflammatory Bowel Disease.,  65  (1.0): [PMID:34957834] [10.1021/acs.jmedchem.1c01746]

49. Li C, Zhou Y, Xu J, Zhou X, Huang Z, Zeng T, Yang X, Tao L, Gou K, Zhong X, Chen Q, Luo Y, Zhao Y..  (2022)  A novel series of teriflunomide derivatives as orally active inhibitors of human dihydroorotate dehydrogenase for the treatment of colorectal carcinoma.,  238  [PMID:35640328] [10.1016/j.ejmech.2022.114489]

50. Sutherland JJ, Yonchev D, Fekete A, Urban L..  (2023)  A preclinical secondary pharmacology resource illuminates target-adverse drug reaction associations of marketed drugs.,  14  (1): [PMID:37468498] [10.1038/s41467-023-40064-9]

51. European Medicines Agency, 

Source

Source(11):

• Scientific Literature
• Clinical Candidates
• FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book)
• USP Dictionary of USAN and International Drug Names
• WHO Anatomical Therapeutic Chemical Classification
• British National Formulary
• SARS-CoV-2 Screening Data 2020-21
• Active Ingredient of a Prodrug
• IMI-CARE SARS-CoV-2 Data
• Fraunhofer HDAC6
• European Medicines Agency