US8629141, 21

ID: ALA3693969

PubChem CID: 71020635

Max Phase: Preclinical

Molecular Formula: C24H24Cl2FN3O2

Molecular Weight: 476.38

Molecule Type: Small molecule

Names and Identifiers

Canonical SMILES:  CNC(=O)[C@@H]1NC2(CCCCC2)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Cl)c1F

Standard InChI:  InChI=1S/C24H24Cl2FN3O2/c1-28-21(31)20-18(14-6-5-7-16(26)19(14)27)24(23(30-20)10-3-2-4-11-23)15-9-8-13(25)12-17(15)29-22(24)32/h5-9,12,18,20,30H,2-4,10-11H2,1H3,(H,28,31)(H,29,32)/t18-,20+,24+/m0/s1

Standard InChI Key:  LHBZDASUSDFFIL-MFSJNOQSSA-N

Molfile:  

     RDKit          2D

 32 36  0  0  1  0  0  0  0  0999 V2000
    6.8176   -2.6427    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    5.7204   -2.1569    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    4.5075   -3.0408    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    4.6350   -4.2340    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
    3.1375   -2.4343    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    2.8256   -0.9670    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    1.2990   -0.7500    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    1.2990    0.7500    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    0.0000    1.5000    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -1.2990    0.7500    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -1.2990   -0.7500    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    0.0000   -1.5000    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    0.7237   -2.1806    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    1.8384   -3.1843    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    1.6816   -4.6768    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    0.2660   -5.1782    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -0.0026   -6.6539    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    1.1412   -7.6244    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    2.5535   -7.1191    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    3.4685   -7.8955    0.0000 Cl  0  0  0  0  0  0  0  0  0  0  0  0
    2.8221   -5.6434    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    3.9519   -5.2388    0.0000 F   0  0  0  0  0  0  0  0  0  0  0  0
   -0.8026   -1.9741    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -1.3528   -0.9076    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
   -1.5002   -3.3020    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   -0.4529   -4.3758    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -0.5504   -5.8713    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    0.6973   -6.7039    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    0.6195   -7.9014    0.0000 Cl  0  0  0  0  0  0  0  0  0  0  0  0
    2.0422   -6.0397    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    2.1394   -4.5428    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    0.8920   -3.7116    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
  1  2  1  0
  2  3  1  0
  3  4  2  0
  5  3  1  1
  5  6  1  0
  6  7  1  0
  7  8  1  0
  8  9  1  0
  9 10  1  0
 10 11  1  0
 11 12  1  0
 12  7  1  0
  7 13  1  0
 13 14  1  0
 14  5  1  0
 14 15  1  6
 15 16  2  0
 16 17  1  0
 17 18  2  0
 18 19  1  0
 19 20  1  0
 19 21  2  0
 21 15  1  0
 21 22  1  0
 13 23  1  6
 23 24  2  0
 23 25  1  0
 25 26  1  0
 26 27  2  0
 27 28  1  0
 28 29  1  0
 28 30  2  0
 30 31  1  0
 31 32  2  0
 32 13  1  0
 32 26  1  0
M  END

Alternative Forms

1. Parent:

   

   ALA3693969

   CID 71020635

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: 476.38

Molecular Weight (Monoisotopic): 475.1230

AlogP: 4.53

#Rotatable Bonds: 2

Polar Surface Area: 70.23

Molecular Species: BASE

HBA: 3

HBD: 3

#RO5 Violations: ┄

HBA (Lipinski): 5

HBD (Lipinski): 3

#RO5 Violations (Lipinski): ┄

CX Acidic pKa: 12.87

CX Basic pKa: 9.07

CX LogP: 4.42

CX LogD: 2.75

Aromatic Rings: 2

Heavy Atoms: 32

QED Weighted: 0.60

Np Likeness Score: -0.13

References

1.  (2014)  Spiro-oxindole MDM2 antagonists, 

2. Aguilar A, Lu J, Liu L, Du D, Bernard D, McEachern D, Przybranowski S, Li X, Luo R, Wen B, Sun D, Wang H, Wen J, Wang G, Zhai Y, Guo M, Yang D, Wang S..  (2017)  Discovery of 4-((3'R,4'S,5'R)-6″-Chloro-4'-(3-chloro-2-fluorophenyl)-1'-ethyl-2″-oxodispiro[cyclohexane-1,2'-pyrrolidine-3',3″-indoline]-5'-carboxamido)bicyclo[2.2.2]octane-1-carboxylic Acid (AA-115/APG-115): A Potent and Orally Active Murine Double Minute 2 (MDM2) Inhibitor in Clinical Development.,  60  (7): [PMID:28339198] [10.1021/acs.jmedchem.6b01665]

3. Yang J, Li Y, Aguilar A, Liu Z, Yang CY, Wang S..  (2019)  Simple Structural Modifications Converting a Bona fide MDM2 PROTAC Degrader into a Molecular Glue Molecule: A Cautionary Tale in the Design of PROTAC Degraders.,  62  (21): [PMID:31560543] [10.1021/acs.jmedchem.9b00846]

4. Raboisson, Pierre P and 12 more authors.  2005-04-01  Structure-based design, synthesis, and biological evaluation of novel 1,4-diazepines as HDM2 antagonists.  [PMID:15780621]

5. Schneekloth, Ashley R AR, Pucheault, Mathieu M, Tae, Hyun Seop HS and Crews, Craig M CM.  2008-11-15  Targeted intracellular protein degradation induced by a small molecule: En route to chemical proteomics.  [PMID:18752944]

6. Hayashi, Ryo R and 5 more authors.  2009-12-01  N-acylpolyamine inhibitors of HDM2 and HDMX binding to p53.  [PMID:19880322]

7. Madden, Michael M and 5 more authors.  2011-03-01  Synthesis of cell-permeable stapled peptide dual inhibitors of the p53-Mdm2/Mdmx interactions via photoinduced cycloaddition.  [PMID:21277201]

8. Ghosh, Pradip P, Zhang, Jiawei J, Shi, Zheng-Zheng ZZ and Li, King K.  2013-04-15  Synthesis and evaluation of an imidazole derivative-fluorescein conjugate.  [PMID:23477941]

9. Zhao, Yujun Y and 12 more authors.  2013-07-11  A potent small-molecule inhibitor of the MDM2-p53 interaction (MI-888) achieved complete and durable tumor regression in mice.  [PMID:23786219]

10. Blackburn, Tim J and 14 more authors.  2013-09-21  Diaryl- and triaryl-pyrrole derivatives: inhibitors of the MDM2-p53 and MDMX-p53 protein-protein interactions†Electronic supplementary information (ESI) available: Experimental details for compound synthesis, analytical data for all compounds and intermediates. Details for the biological evaluation. Further details for the modeling. Table of combustion analysis data. See DOI: 10.1039/c3md00161jClick here for additional data file.  [PMID:24078862]

11. Li, Jin J and 14 more authors.  2014-06-15  Discovery of 1-arylpyrrolidone derivatives as potent p53-MDM2 inhibitors based on molecule fusing strategy.  [PMID:24813735]

12. Zheng, Guang-hui GH and 7 more authors.  2014-06-23  Design, synthesis and in vitro and in vivo antitumour activity of 3-benzylideneindolin-2-one derivatives, a novel class of small-molecule inhibitors of the MDM2-p53 interaction.  [PMID:24852275]

13. Rew, Yosup Y and 34 more authors.  2014-12-26  Discovery of AM-7209, a potent and selective 4-amidobenzoic acid inhibitor of the MDM2-p53 interaction.  [PMID:25384157]

14. Zhao, Yujun Y, Aguilar, Angelo A, Bernard, Denzil D and Wang, Shaomeng S.  2015-02-12  Small-molecule inhibitors of the MDM2-p53 protein-protein interaction (MDM2 Inhibitors) in clinical trials for cancer treatment.  [PMID:25396320]

15. Aguilar, Angelo and 7 more authors.  2014-12-26  Design of chemically stable, potent, and efficacious MDM2 inhibitors that exploit the retro-mannich ring-opening-cyclization reaction mechanism in spiro-oxindoles.  [PMID:25496041]

16. Neochoritis, Constantinos G and 8 more authors.  2015-12-15  2,30-Bis(10H-indole) heterocycles: New p53/MDM2/MDMX antagonists.  [PMID:26584879]

17. Daniele, Simona S and 12 more authors.  2016-05-26  Lead Optimization of 2-Phenylindolylglyoxylyldipeptide Murine Double Minute (MDM)2/Translocator Protein (TSPO) Dual Inhibitors for the Treatment of Gliomas.  [PMID:27050782]

18. Aguilar, Angelo and 17 more authors.  2017-04-13  Discovery of 4-((3'R,4'S,5'R)-6″-Chloro-4'-(3-chloro-2-fluorophenyl)-1'-ethyl-2″-oxodispiro[cyclohexane-1,2'-pyrrolidine-3',3″-indoline]-5'-carboxamido)bicyclo[2.2.2]octane-1-carboxylic Acid (AA-115/APG-115): A Potent and Orally Active Murine Double Minute 2 (MDM2) Inhibitor in Clinical Development.  [PMID:28339198]

19. Giustiniano, Mariateresa M and 18 more authors.  2017-10-12  Computer-Aided Identification and Lead Optimization of Dual Murine Double Minute 2 and 4 Binders: Structure-Activity Relationship Studies and Pharmacological Activity.  [PMID:28921985]

20. Merlino, Francesco F and 20 more authors.  2018-06-14  Simultaneous Targeting of RGD-Integrins and Dual Murine Double Minute Proteins in Glioblastoma Multiforme.  [PMID:29775303]

21. Niazi, Sarfaraj S, Purohit, Madhusudan M and Niazi, Javed H JH.  2018-10-05  Role of p53 circuitry in tumorigenesis: A brief review.  [PMID:30199707]

22. Wang, Bo B and 5 more authors.  2019-08-15  Development of selective small molecule MDM2 degraders based on nutlin.  [PMID:31128449]

23. Sang, Peng and 10 more authors.  2020-02-13  α-Helix-Mimicking Sulfono-γ-AApeptide Inhibitors for p53-MDM2/MDMX Protein-Protein Interactions.  [PMID:31971801]

Source

Source(2):

• Scientific Literature
• BindingDB Database