ID: ALA559147

Max Phase: Preclinical

Molecular Formula: C14H21N3O

Molecular Weight: 247.34

Molecule Type: Small molecule

Representations

Synonyms (1): Y-27632
Synonyms from Alternative Forms(1):

Canonical SMILES:  C[C@@H](N)[C@H]1CC[C@H](C(=O)Nc2ccncc2)CC1

Standard InChI:  InChI=1S/C14H21N3O/c1-10(15)11-2-4-12(5-3-11)14(18)17-13-6-8-16-9-7-13/h6-12H,2-5,15H2,1H3,(H,16,17,18)/t10-,11-,12-/m1/s1

Standard InChI Key:  IYOZTVGMEWJPKR-IJLUTSLNSA-N

Molecule Features

Natural Product: No

Oral: No

Chemical Probe: No

Parenteral: No

Molecule Type: Small molecule

Topical: No

First In Class: No

Black Box: No

Chirality: No

Availability: No

Prodrug: No

Properties

Molecular Weight: 247.34

Molecular Weight (Monoisotopic): 247.1685

AlogP: 2.17

#Rotatable Bonds: 3

Polar Surface Area: 68.01

Molecular Species: BASE

HBA: 3

HBD: 2

#RO5 Violations: 0

HBA (Lipinski): 4

HBD (Lipinski): 3

#RO5 Violations (Lipinski): 0

CX Acidic pKa: 13.44

CX Basic pKa: 10.45

CX LogP: 1.34

CX LogD: -1.41

Aromatic Rings: 1

Heavy Atoms: 18

QED Weighted: 0.86

Np Likeness Score: -1.25

References

1. McGovern SL, Shoichet BK..  (2003)  Kinase inhibitors: not just for kinases anymore.,  46  (8): [PMID:12672248] [10.1021/jm020427b]

2. Kuder CH, Neighbors JD, Hohl RJ, Wiemer DF..  (2009)  Synthesis and biological activity of a fluorescent schweinfurthin analogue.,  17  (13): [PMID:19464190] [10.1016/j.bmc.2009.04.071]

3. Bain J, Plater L, Elliott M, Shpiro N, Hastie CJ, McLauchlan H, Klevernic I, Arthur JS, Alessi DR, Cohen P..  (2007)  The selectivity of protein kinase inhibitors: a further update.,  408  (3): [PMID:17850214] [10.1042/bj20070797]

4. Jacobs M, Hayakawa K, Swenson L, Bellon S, Fleming M, Taslimi P, Doran J..  (2006)  The structure of dimeric ROCK I reveals the mechanism for ligand selectivity.,  281  (1): [PMID:16249185] [10.1074/jbc.m508847200]

5. Ho KK, Beasley JR, Belanger L, Black D, Chan JH, Dunn D, Hu B, Klon A, Kultgen SG, Ohlmeyer M, Parlato SM, Ray PC, Pham Q, Rong Y, Roughton AL, Walker TL, Wright J, Xu K, Xu Y, Zhang L, Webb M..  (2009)  Triazine and pyrimidine based ROCK inhibitors with efficacy in spontaneous hypertensive rat model.,  19  (21): [PMID:19800787] [10.1016/j.bmcl.2009.09.046]

6. Morwick T, Büttner FH, Cywin CL, Dahmann G, Hickey E, Jakes S, Kaplita P, Kashem MA, Kerr S, Kugler S, Mao W, Marshall D, Paw Z, Shih CK, Wu F, Young E..  (2010)  Hit to lead account of the discovery of bisbenzamide and related ureidobenzamide inhibitors of Rho kinase.,  53  (2): [PMID:20000469] [10.1021/jm9014263]

7. MacDonald ML, Lamerdin J, Owens S, Keon BH, Bilter GK, Shang Z, Huang Z, Yu H, Dias J, Minami T, Michnick SW, Westwick JK..  (2006)  Identifying off-target effects and hidden phenotypes of drugs in human cells.,  2  (6): [PMID:16680159] [10.1038/nchembio790]

8. Davies SP, Reddy H, Caivano M, Cohen P..  (2000)  Specificity and mechanism of action of some commonly used protein kinase inhibitors.,  351  (1): [PMID:10998351] [10.1042/0264-6021:3510095]

9. Ray P, Wright J, Adam J, Bennett J, Boucharens S, Black D, Cook A, Brown AR, Epemolu O, Fletcher D, Haunso A, Huggett M, Jones P, Laats S, Lyons A, Mestres J, de Man J, Morphy R, Rankovic Z, Sherborne B, Sherry L, van Straten N, Westwood P, Zaman GZ..  (2011)  Fragment-based discovery of 6-substituted isoquinolin-1-amine based ROCK-I inhibitors.,  21  (1): [PMID:21145740] [10.1016/j.bmcl.2010.11.060]

10. PubChem BioAssay data set, 

11. Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program. DrugMatrix in vitro pharmacology data, 

12. Doe C, Bentley R, Behm DJ, Lafferty R, Stavenger R, Jung D, Bamford M, Panchal T, Grygielko E, Wright LL, Smith GK, Chen Z, Webb C, Khandekar S, Yi T, Kirkpatrick R, Dul E, Jolivette L, Marino JP, Willette R, Lee D, Hu E..  (2007)  Novel Rho kinase inhibitors with anti-inflammatory and vasodilatory activities.,  320  (1): [PMID:17018693] [10.1124/jpet.106.110635]

13. Jester BW, Gaj A, Shomin CD, Cox KJ, Ghosh I..  (2012)  Testing the promiscuity of commercial kinase inhibitors against the AGC kinase group using a split-luciferase screen.,  55  (4): [PMID:22257127] [10.1021/jm201265f]

14. Gao Y, Davies SP, Augustin M, Woodward A, Patel UA, Kovelman R, Harvey KJ..  (2013)  A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery.,  451  (2): [PMID:23398362] [10.1042/bj20121418]

15. PubChem BioAssay data set, 

16. Bell JL, Haak AJ, Wade SM, Kirchhoff PD, Neubig RR, Larsen SD..  (2013)  Optimization of novel nipecotic bis(amide) inhibitors of the Rho/MKL1/SRF transcriptional pathway as potential anti-metastasis agents.,  23  (13): [PMID:23707258] [10.1016/j.bmcl.2013.04.080]

17. Boland S, Defert O, Alen J, Bourin A, Castermans K, Kindt N, Boumans N, Panitti L, Van de Velde S, Stalmans I, Leysen D..  (2013)  3-[2-(Aminomethyl)-5-[(pyridin-4-yl)carbamoyl]phenyl] benzoates as soft ROCK inhibitors.,  23  (23): [PMID:24119557] [10.1016/j.bmcl.2013.09.040]

18. Unpublished dataset, 

19. Pireddu R, Forinash KD, Sun NN, Martin MP, Sung SS, Alexander B, Zhu JY, Guida WC, Schönbrunn E, Sebti SM, Lawrence NJ..  (2012)  Pyridylthiazole-based ureas as inhibitors of Rho associated protein kinases (ROCK1 and 2).,  3  (6): [PMID:23275831] [10.1039/c2md00320a]

20. Shaw D, Hollingworth G, Soldermann N, Sprague E, Schuler W, Vangrevelinghe E, Duggan N, Thomas M, Kosaka T, Waters N, van Eis MJ..  (2014)  Novel ROCK inhibitors for the treatment of pulmonary arterial hypertension.,  24  (20): [PMID:25248678] [10.1016/j.bmcl.2014.09.002]

21. Boland S, Bourin A, Alen J, Geraets J, Schroeders P, Castermans K, Kindt N, Boumans N, Panitti L, Fransen S, Vanormelingen J, Stassen JM, Leysen D, Defert O..  (2015)  Design, synthesis, and biological evaluation of novel, highly active soft ROCK inhibitors.,  58  (10): [PMID:25898023] [10.1021/acs.jmedchem.5b00308]

22. Fedorov O, Marsden B, Pogacic V, Rellos P, Müller S, Bullock AN, Schwaller J, Sundström M, Knapp S..  (2007)  A systematic interaction map of validated kinase inhibitors with Ser/Thr kinases.,  104  (51): [PMID:18077363] [10.1073/pnas.0708800104]

23. Green J, Cao J, Bandarage UK, Gao H, Court J, Marhefka C, Jacobs M, Taslimi P, Newsome D, Nakayama T, Shah S, Rodems S..  (2015)  Design, Synthesis, and Structure-Activity Relationships of Pyridine-Based Rho Kinase (ROCK) Inhibitors.,  58  (12): [PMID:26039570] [10.1021/acs.jmedchem.5b00424]

24. Domokos D, Fülöp F, Falkay G, Gáspár R..  (2018)  Effects of newly synthetized isoquinoline derivatives on rat uterine contractility and ROCK II activity.,  28  (3): [PMID:29269216] [10.1016/j.bmcl.2017.12.017]

25. Verga D, N'Guyen CH, Dakir M, Coll JL, Teulade-Fichou MP, Molla A..  (2018)  Polyheteroaryl Oxazole/Pyridine-Based Compounds Selected in Vitro as G-Quadruplex Ligands Inhibit Rock Kinase and Exhibit Antiproliferative Activity.,  61  (23): [PMID:30457335] [10.1021/acs.jmedchem.8b01023]

26. Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek.  (2020)  Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection,  [10.21203/rs.3.rs-23951/v1]

27. 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]

28. 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]

29. 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]

30. 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]

31. Kesar S, Paliwal S, Mishra P, Madan K, Chauhan M, Chauhan N, Verma K, Sharma S..  (2020)  Identification of Novel Rho-Kinase-II Inhibitors with Vasodilatory Activity.,  11  (9): [PMID:32944136] [10.1021/acsmedchemlett.0c00126]

32. 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]

33. Ladduwahetty T, Lee MR, Maillard MC, Cachope R, Todd D, Barnes M, Beaumont V, Chauhan A, Gallati C, Haughan AF, Kempf G, Luckhurst CA, Matthews K, McAllister G, Mitchell P, Patel H, Rose M, Saville-Stones E, Steinbacher S, Stott AJ, Thatcher E, Tierney J, Urbonas L, Munoz-Sanjuan I, Dominguez C..  (2022)  Identification of a Potent, Selective, and Brain-Penetrant Rho Kinase Inhibitor and its Activity in a Mouse Model of Huntington's Disease.,  65  (14.0): [PMID:35816678] [10.1021/acs.jmedchem.2c00474]

34. Xie Z, Yang X, Duan Y, Han J, Liao C..  (2021)  Small-Molecule Kinase Inhibitors for the Treatment of Nononcologic Diseases.,  64  (3.0): [PMID:33481605] [10.1021/acs.jmedchem.0c01511]

35. Mancini RS, Barden CJ, Weaver DF, Reed MA..  (2021)  Furazans in Medicinal Chemistry.,  64  (4.0): [PMID:33569941] [10.1021/acs.jmedchem.0c01901]

36. Feng Y, LoGrasso PV, Defert O, Li R..  (2016)  Rho Kinase (ROCK) Inhibitors and Their Therapeutic Potential.,  59  (6): [PMID:26486225] [10.1021/acs.jmedchem.5b00683]

Source

Source(6):

• Scientific Literature
• PubChem BioAssays
• DrugMatrix
• Gene Expression Atlas Compounds
• SARS-CoV-2 Screening Data 2020-21
• Fraunhofer HDAC6