1-(4-(1-ethyl-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl)phenyl)-3-phenylurea

ID: ALA1089116

PubChem CID: 46885625

Max Phase: Preclinical

Molecular Formula: C25H22N6O

Molecular Weight: 422.49

Molecule Type: Small molecule

Names and Identifiers

Canonical SMILES:  CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1

Standard InChI:  InChI=1S/C25H22N6O/c1-2-31-16-22(20-12-14-26-24-21(20)13-15-27-24)23(30-31)17-8-10-19(11-9-17)29-25(32)28-18-6-4-3-5-7-18/h3-16H,2H2,1H3,(H,26,27)(H2,28,29,32)

Standard InChI Key:  CZVVMRNEBRFYTL-UHFFFAOYSA-N

Molfile:  

     RDKit          2D

 32 36  0  0  0  0  0  0  0  0999 V2000
   -1.9373  -18.9515    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -1.9585  -19.7789    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -1.2540  -20.2065    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -0.5279  -19.8126    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -0.5113  -18.9816    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -1.2164  -18.5582    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    0.2108  -18.5824    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    0.8832  -19.0657    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    1.5499  -18.5797    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    1.2936  -17.7953    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    0.4687  -17.7969    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    1.7774  -17.1271    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    2.5981  -17.2118    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    0.8865  -19.8907    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    0.1730  -20.3023    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    0.1758  -21.1266    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    0.8925  -21.5372    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    1.6014  -20.2945    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    1.6101  -21.1140    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    2.3921  -21.3590    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    2.8668  -20.6909    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    2.3780  -20.0331    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -2.6825  -20.1742    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   -2.7021  -20.9991    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -3.4262  -21.3945    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   -1.9976  -21.4285    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
   -4.1306  -20.9651    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -4.1099  -20.1395    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -5.5367  -20.1022    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -5.5583  -20.9279    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -4.8103  -19.7103    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -4.8535  -21.3617    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
  7  8  1  0
 15 16  1  0
  3  4  2  0
 16 17  2  0
 17 19  1  0
 18 14  1  0
 18 19  2  0
  4  5  1  0
  2  3  1  0
  8  9  2  0
  9 10  1  0
 19 20  1  0
 20 21  1  0
 21 22  2  0
 22 18  1  0
 10 11  1  0
  2 23  1  0
 11  7  2  0
 23 24  1  0
  5  6  2  0
 24 25  1  0
 10 12  1  0
 24 26  2  0
  6  1  1  0
 25 27  1  0
 27 28  2  0
 12 13  1  0
 29 30  1  0
  1  2  2  0
  8 14  1  0
  5  7  1  0
 14 15  2  0
 27 32  1  0
 28 31  1  0
 31 29  2  0
 30 32  2  0
M  END

Alternative Forms

1. Parent:

   

   ALA1089116

   N-{4-[1-Ethyl-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]phenyl}-N'-phenylurea

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

Calculated Properties

Molecular Weight: 422.49

Molecular Weight (Monoisotopic): 422.1855

AlogP: 5.76

#Rotatable Bonds: 5

Polar Surface Area: 87.63

Molecular Species: NEUTRAL

HBA: 4

HBD: 3

#RO5 Violations: 1

HBA (Lipinski): 7

HBD (Lipinski): 3

#RO5 Violations (Lipinski): 1

CX Acidic pKa: 11.38

CX Basic pKa: 2.87

CX LogP: 4.83

CX LogD: 4.83

Aromatic Rings: 5

Heavy Atoms: 32

QED Weighted: 0.34

Np Likeness Score: -1.29

References

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2. Adams ND, Adams JL, Burgess JL, Chaudhari AM, Copeland RA, Donatelli CA, Drewry DH, Fisher KE, Hamajima T, Hardwicke MA, Huffman WF, Koretke-Brown KK, Lai ZV, McDonald OB, Nakamura H, Newlander KA, Oleykowski CA, Parrish CA, Patrick DR, Plant R, Sarpong MA, Sasaki K, Schmidt SJ, Silva DJ, Sutton D, Tang J, Thompson CS, Tummino PJ, Wang JC, Xiang H, Yang J, Dhanak D..  (2010)  Discovery of GSK1070916, a potent and selective inhibitor of Aurora B/C kinase.,  53  (10): [PMID:20420387] [10.1021/jm901870q]

3. Fancelli, Daniele D and 24 more authors.  2006-11-30  1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazoles: identification of a potent Aurora kinase inhibitor with a favorable antitumor kinase inhibition profile.  [PMID:17125279]

4. Yang, Jing J and 11 more authors.  2007-09-15  AZD1152, a novel and selective aurora B kinase inhibitor, induces growth arrest, apoptosis, and sensitization for tubulin depolymerizing agent or topoisomerase II inhibitor in human acute leukemia cells in vitro and in vivo.  [PMID:17495131]

5. McDermott, Ultan U and 24 more authors.  2007-12-11  Identification of genotype-correlated sensitivity to selective kinase inhibitors by using high-throughput tumor cell line profiling.  [PMID:18077425]

6. Weiss, Matthew M MM and 30 more authors.  2008-03-27  Evaluation of a series of naphthamides as potent, orally active vascular endothelial growth factor receptor-2 tyrosine kinase inhibitors.  [PMID:18324759]

7. Shiotsu, Yukimasa Y and 16 more authors.  2009-08-20  KW-2449, a novel multikinase inhibitor, suppresses the growth of leukemia cells with FLT3 mutations or T315I-mutated BCR/ABL translocation.  [PMID:19541823]

8. Zarrinkar, Patrick P PP and 15 more authors.  2009-10-01  AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML).  [PMID:19654408]

9. Shimomura, Toshiyasu T and 14 more authors.  2010-01  MK-5108, a highly selective Aurora-A kinase inhibitor, shows antitumor activity alone and in combination with docetaxel.  [PMID:20053775]

10. Adams, Nicholas D ND and 31 more authors.  2010-05-27  Discovery of GSK1070916, a potent and selective inhibitor of Aurora B/C kinase.  [PMID:20420387]

11. Bavetsias, Vassilios V and 21 more authors.  2010-07-22  Imidazo[4,5-b]pyridine derivatives as inhibitors of Aurora kinases: lead optimization studies toward the identification of an orally bioavailable preclinical development candidate.  [PMID:20565112]

12. Payton, Marc M and 20 more authors.  2010-12-01  Preclinical evaluation of AMG 900, a novel potent and highly selective pan-aurora kinase inhibitor with activity in taxane-resistant tumor cell lines.  [PMID:20935223]

13. Medina, Jesús R JR and 24 more authors.  2011-03-24  Structure-based design of potent and selective 3-phosphoinositide-dependent kinase-1 (PDK1) inhibitors.  [PMID:21341675]

14. Mollard, Alexis A and 8 more authors.  2011-12-08  Design, Synthesis and Biological Evaluation of a Series of Novel Axl Kinase Inhibitors.  [PMID:22247788]

15. Lawrence, Harshani R and 14 more authors.  2012-09-13  Development of o-chlorophenyl substituted pyrimidines as exceptionally potent aurora kinase inhibitors.  [PMID:22803810]

16. Elkins, Jonathan M; Santaguida, Stefano; Musacchio, Andrea and Knapp, Stefan.  2012-09-13  Crystal structure of human aurora B in complex with INCENP and VX-680.  [PMID:22920039]

17. Glaser, Keith B KB and 22 more authors.  2012-12  Preclinical characterization of ABT-348, a kinase inhibitor targeting the aurora, vascular endothelial growth factor receptor/platelet-derived growth factor receptor, and Src kinase families.  [PMID:22935731]

18. Weïwer, Michel M and 12 more authors.  2012-12-13  A Potent and Selective Quinoxalinone-Based STK33 Inhibitor Does Not Show Synthetic Lethality in KRAS-Dependent Cells.  [PMID:23256033]

19. Li, Jie J and 6 more authors.  2013-07  A thienopyrimidine derivative induces growth inhibition and apoptosis in human cancer cell lines via inhibiting Aurora B kinase activity.  [PMID:23707920]

20. Shiao, Hui-Yi HY and 18 more authors.  2013-07-11  Optimization of ligand and lipophilic efficiency to identify an in vivo active furano-pyrimidine Aurora kinase inhibitor.  [PMID:23808327]

21. Sampson, Peter B PB and 23 more authors.  2015-01-08  The discovery of Polo-like kinase 4 inhibitors: design and optimization of spiro[cyclopropane-1,3'[3H]indol]-2'(1'H).ones as orally bioavailable antitumor agents.  [PMID:24867403]

22. Alder, Catherine M CM and 18 more authors.  2013-10-10  Identification of a Novel and Selective Series of Itk Inhibitors via a Template-Hopping Strategy.  [PMID:24900590]

23. Jagtap, Ajit Dhananjay AD and 8 more authors.  2014-10-06  Novel acylureidoindolin-2-one derivatives as dual Aurora B/FLT3 inhibitors for the treatment of acute myeloid leukemia.  [PMID:25089810]

24. Carry, Jean-Christophe JC and 32 more authors.  2015-01-08  SAR156497, an exquisitely selective inhibitor of aurora kinases.  [PMID:25369539]

25. An, Ying Y and 7 more authors.  2016-07-01  Design and synthesis of novel benzoxazole analogs as Aurora B kinase inhibitors.  [PMID:27209235]

26. Klaeger, Susan S and 47 more authors.  2017-12-01  The target landscape of clinical kinase drugs.  [PMID:29191878]

27. Barker, Michael D MD and 11 more authors.  2018-11-15  Discovery of potent and selective Spleen Tyrosine Kinase inhibitors for the topical treatment of inflammatory skin disease.  [PMID:30249354]

28. Narayan, Satya S and 7 more authors.  2019-01-01  ASR352, A potent anticancer agent: Synthesis, preliminary SAR, and biological activities against colorectal cancer bulk, 5-fluorouracil/oxaliplatin resistant and stem cells.  [PMID:30384048]

29. Fan, Chengcheng and 7 more authors.  2020-03-15  Design, synthesis, biological evaluation of 6-(2-amino-1H-benzo[d]imidazole-6-yl)quinazolin-4(3H)-one derivatives as novel anticancer agents with Aurora kinase inhibition.  [PMID:32058239]

30. Lakkaniga, Naga Rajiv and 5 more authors.  2020-10-01  Discovery of SP-96, the first non-ATP-competitive Aurora Kinase B inhibitor, for reduced myelosuppression.  [PMID:32717530]

Source

Source(1):

• Scientific Literature