N-(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5-fluoro-4-(5-fluoro-1-methyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)pyrimidin-2-amine

ID: ALA4212542

PubChem CID: 129102594

Max Phase: Preclinical

Molecular Formula: C27H30F2N8

Molecular Weight: 504.59

Molecule Type: Small molecule

Names and Identifiers

Canonical SMILES:  CCN1CCN(Cc2ccc(Nc3ncc(F)c(-c4cc(F)c5nc6n(c5c4)C(C)CC6)n3)nc2)CC1

Standard InChI:  InChI=1S/C27H30F2N8/c1-3-35-8-10-36(11-9-35)16-18-5-6-23(30-14-18)32-27-31-15-21(29)25(34-27)19-12-20(28)26-22(13-19)37-17(2)4-7-24(37)33-26/h5-6,12-15,17H,3-4,7-11,16H2,1-2H3,(H,30,31,32,34)

Standard InChI Key:  YCANTYAOGZQCIG-UHFFFAOYSA-N

Molfile:  

     RDKit          2D

 37 42  0  0  0  0  0  0  0  0999 V2000
   16.0215  -13.2536    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   16.7359  -12.8411    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   17.4504  -13.2536    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   17.4504  -14.0786    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   16.7359  -14.4911    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   16.0215  -14.0786    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   15.3070  -12.8411    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   19.8714  -10.7104    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   20.2069  -11.4641    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   19.5938  -12.0161    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   18.8794  -11.6036    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   19.0509  -10.7966    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   20.0429   -9.9034    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   19.3284   -9.4909    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   18.7153  -10.0430    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   18.1649  -12.0161    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   18.1649  -12.8411    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   18.8794  -13.2536    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   19.5938  -12.8411    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   17.9084   -9.8714    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   20.3083  -13.2536    0.0000 F   0  0  0  0  0  0  0  0  0  0  0  0
   18.1649  -14.4911    0.0000 F   0  0  0  0  0  0  0  0  0  0  0  0
   14.5925  -13.2536    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   14.5925  -14.0786    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   13.8781  -14.4911    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   13.1636  -14.0786    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   13.1636  -13.2536    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   13.8781  -12.8411    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   12.4491  -14.4911    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   11.7346  -14.0786    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   11.0202  -14.4911    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   10.3057  -14.0786    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   10.3057  -13.2536    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   11.0202  -12.8411    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   11.7346  -13.2536    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    9.5912  -12.8411    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    8.8768  -13.2536    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
  1  2  1  0
  2  3  2  0
  3  4  1  0
  4  5  2  0
  5  6  1  0
  1  6  2  0
  1  7  1  0
  8  9  2  0
  9 10  1  0
 10 11  1  0
 11 12  1  0
  8 12  1  0
 13 14  1  0
 14 15  1  0
 12 15  1  0
  8 13  1  0
 16 17  1  0
 17 18  2  0
 18 19  1  0
 10 19  2  0
 11 16  2  0
 15 20  1  0
 19 21  1  0
  3 17  1  0
  4 22  1  0
 23 24  1  0
 24 25  2  0
 25 26  1  0
 26 27  2  0
 27 28  1  0
 23 28  2  0
 30 31  1  0
 31 32  1  0
 32 33  1  0
 33 34  1  0
 34 35  1  0
 30 35  1  0
 36 37  1  0
 33 36  1  0
 29 30  1  0
 26 29  1  0
  7 23  1  0
M  END

Alternative Forms

1. Parent:

   

   ALA4212542

   ---

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: 504.59

Molecular Weight (Monoisotopic): 504.2561

AlogP: 4.55

#Rotatable Bonds: 6

Polar Surface Area: 75.00

Molecular Species: NEUTRAL

HBA: 8

HBD: 1

#RO5 Violations: 1

HBA (Lipinski): 8

HBD (Lipinski): 1

#RO5 Violations (Lipinski): 1

CX Acidic pKa: 10.27

CX Basic pKa: 7.94

CX LogP: 4.29

CX LogD: 3.63

Aromatic Rings: 4

Heavy Atoms: 37

QED Weighted: 0.41

Np Likeness Score: -1.36

References

1. Wang Y, Liu WJ, Yin L, Li H, Chen ZH, Zhu DX, Song XQ, Cheng ZZ, Song P, Wang Z, Li ZG..  (2018)  Design and synthesis of 4-(2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)-N-(5-(piperazin-1-ylmethyl)pyridine-2-yl)pyrimidin-2-amine as a highly potent and selective cyclin-dependent kinases 4 and 6 inhibitors and the discovery of structure-activity relationships.,  28  (5): [PMID:29429832] [10.1016/j.bmcl.2017.12.068]

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3. Leost, M M and 14 more authors.  2000-10  Paullones are potent inhibitors of glycogen synthase kinase-3beta and cyclin-dependent kinase 5/p25.  [PMID:10998059]

4. Lane, M E ME and 9 more authors.  2001-08-15  A novel cdk2-selective inhibitor, SU9516, induces apoptosis in colon carcinoma cells.  [PMID:11507069]

5. Bramson, H N HN and 20 more authors.  2001-12-06  Oxindole-based inhibitors of cyclin-dependent kinase 2 (CDK2): design, synthesis, enzymatic activities, and X-ray crystallographic analysis.  [PMID:11728181]

6. Mettey, Yvette Y and 9 more authors.  2003-01-16  Aloisines, a new family of CDK/GSK-3 inhibitors. SAR study, crystal structure in complex with CDK2, enzyme selectivity, and cellular effects.  [PMID:12519061]

7. Ring, David B DB and 12 more authors.  2003-03  Selective glycogen synthase kinase 3 inhibitors potentiate insulin activation of glucose transport and utilization in vitro and in vivo.  [PMID:12606497]

8. Sayle, Kerry L KL and 16 more authors.  2003-09-15  Structure-based design of 2-arylamino-4-cyclohexylmethyl-5-nitroso-6-aminopyrimidine inhibitors of cyclin-dependent kinases 1 and 2.  [PMID:12941338]

9. Kuo, Gee-Hong GH and 13 more authors.  2005-03-24  Synthesis and discovery of pyrazine-pyridine biheteroaryl as a novel series of potent vascular endothelial growth factor receptor-2 inhibitors.  [PMID:15771433]

10. Lin, Ronghui R and 11 more authors.  2005-06-30  1-Acyl-1H-[1,2,4]triazole-3,5-diamine analogues as novel and potent anticancer cyclin-dependent kinase inhibitors: synthesis and evaluation of biological activities.  [PMID:15974571]

11. Pennati, Marzia M and 12 more authors.  2005-09  Potentiation of paclitaxel-induced apoptosis by the novel cyclin-dependent kinase inhibitor NU6140: a possible role for survivin down-regulation.  [PMID:16170024]

12. Sridhar, Jayalakshmi J, Akula, Nagaraju N and Pattabiraman, Nagarajan N.  2006-03-24  Selectivity and potency of cyclin-dependent kinase inhibitors.  [PMID:16584130]

13. DePinto, Wanda W and 19 more authors.  2006-11  In vitro and in vivo activity of R547: a potent and selective cyclin-dependent kinase inhibitor currently in phase I clinical trials.  [PMID:17121911]

14. Joshi, Kalpana S KS and 7 more authors.  2007-03  In vitro antitumor properties of a novel cyclin-dependent kinase inhibitor, P276-00.  [PMID:17363486]

15. Jones, Clifford D CD and 18 more authors.  2008-12-15  The discovery of AZD5597, a potent imidazole pyrimidine amide CDK inhibitor suitable for intravenous dosing.  [PMID:18996007]

16. Squires, Matthew S MS and 7 more authors.  2009-02  Biological characterization of AT7519, a small-molecule inhibitor of cyclin-dependent kinases, in human tumor cell lines.  [PMID:19174555]

17. Goh, K C KC and 15 more authors.  2012-02  TG02, a novel oral multi-kinase inhibitor of CDKs, JAK2 and FLT3 with potent anti-leukemic properties.  [PMID:21860433]

18. Cirstea, D D and 15 more authors.  2013-12  Small-molecule multi-targeted kinase inhibitor RGB-286638 triggers P53-dependent and -independent anti-multiple myeloma activity through inhibition of transcriptional CDKs.  [PMID:23807770]

19. Martin, Mathew P MP, Olesen, Sanne H SH, Georg, Gunda I GI and Schönbrunn, Ernst E.  2013-11-15  Cyclin-dependent kinase inhibitor dinaciclib interacts with the acetyl-lysine recognition site of bromodomains.  [PMID:24007471]

20. Paiva, Cody C and 8 more authors.  2015  Cyclin-Dependent Kinase Inhibitor P1446A Induces Apoptosis in a JNK/p38 MAPK-Dependent Manner in Chronic Lymphocytic Leukemia B-Cells.  [PMID:26606677]

21. Sonawane, Yogesh A and 5 more authors.  2016-10-13  Cyclin Dependent Kinase 9 Inhibitors for Cancer Therapy.  [PMID:27171036]

22. Patel, Hetal H and 15 more authors.  2018-06  ICEC0942, an Orally Bioavailable Selective Inhibitor of CDK7 for Cancer Treatment.  [PMID:29545334]

23. Wang, Yiting Y and 6 more authors.  2018-07-23  Design, synthesis and biological evaluation of pyrimidine derivatives as novel CDK2 inhibitors that induce apoptosis and cell cycle arrest in breast cancer cells.  [PMID:29853338]

24. Teng, Yuou and 10 more authors.  2019-12-01  Recent advances in the development of cyclin-dependent kinase 7 inhibitors.  [PMID:31514062]

25. Wu, Tizhi and 6 more authors.  2020-11-25  Recent Developments in the Biology and Medicinal Chemistry of CDK9 Inhibitors: An Update.  [PMID:32866383]

Source

Source(1):

• Scientific Literature