2-((1r,4r)-4-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexylamino)acetic acid

ID: ALA4066401

PubChem CID: 118105340

Max Phase: Preclinical

Molecular Formula: C26H27N5O3

Molecular Weight: 457.53

Molecule Type: Small molecule

Names and Identifiers

Canonical SMILES:  Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2[C@H]1CC[C@H](NCC(=O)O)CC1

Standard InChI:  InChI=1S/C26H27N5O3/c27-25-24-22(17-6-12-21(13-7-17)34-20-4-2-1-3-5-20)15-31(26(24)30-16-29-25)19-10-8-18(9-11-19)28-14-23(32)33/h1-7,12-13,15-16,18-19,28H,8-11,14H2,(H,32,33)(H2,27,29,30)/t18-,19-

Standard InChI Key:  UPOHPTDDNIQADZ-WGSAOQKQSA-N

Molfile:  

     RDKit          2D

 34 38  0  0  0  0  0  0  0  0999 V2000
   14.5429   -6.7191    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   14.5418   -7.5386    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   15.2498   -7.9476    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   15.2480   -6.3102    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   15.9567   -6.7155    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   15.9615   -7.5387    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   16.7459   -7.7885    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   17.2259   -7.1196    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   16.7381   -6.4566    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   16.9860   -5.6779    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   17.7836   -5.5088    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   18.0316   -4.7310    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   17.4810   -4.1260    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   16.6791   -4.3041    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   16.4348   -5.0817    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   17.0007   -8.5619    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   16.4554   -9.1718    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   16.7094   -9.9447    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   17.5092  -10.1142    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   18.0546   -9.5043    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   17.8001   -8.7250    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   17.7626  -10.8854    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   17.7279   -3.3470    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
   18.5260   -3.1713    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   19.0756   -3.7753    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   19.8730   -3.6002    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   20.1206   -2.8205    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   19.5647   -2.2158    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   18.7693   -2.3941    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   15.2456   -5.4930    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   18.5478  -11.0940    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   18.7610  -11.8829    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   19.5508  -12.0927    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
   18.1844  -12.4620    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
  1  2  2  0
  2  3  1  0
  3  6  2  0
  5  4  2  0
  4  1  1  0
  5  6  1  0
  6  7  1  0
  7  8  1  0
  8  9  2  0
  9  5  1  0
  9 10  1  0
 10 11  2  0
 11 12  1  0
 12 13  2  0
 13 14  1  0
 14 15  2  0
 15 10  1  0
 16 17  1  0
 16 21  1  0
 17 18  1  0
 18 19  1  0
 19 20  1  0
 20 21  1  0
 16  7  1  1
 19 22  1  6
 13 23  1  0
 23 24  1  0
 24 25  2  0
 25 26  1  0
 26 27  2  0
 27 28  1  0
 28 29  2  0
 29 24  1  0
  4 30  1  0
 22 31  1  0
 31 32  1  0
 32 33  2  0
 32 34  1  0
M  END

Alternative Forms

1. Parent:

   

   ALA4066401

   2-[[4-[4-Amino-5-(4-phenoxyphenyl)pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexyl]amino]acetic acid

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: 457.53

Molecular Weight (Monoisotopic): 457.2114

AlogP: 4.63

#Rotatable Bonds: 7

Polar Surface Area: 115.29

Molecular Species: ZWITTERION

HBA: 7

HBD: 3

#RO5 Violations: ┄

HBA (Lipinski): 8

HBD (Lipinski): 4

#RO5 Violations (Lipinski): ┄

CX Acidic pKa: 1.18

CX Basic pKa: 10.74

CX LogP: 1.38

CX LogD: 1.20

Aromatic Rings: 4

Heavy Atoms: 34

QED Weighted: 0.37

Np Likeness Score: -0.43

References

1. Yuki H, Kikuzato K, Koda Y, Mikuni J, Tomabechi Y, Kukimoto-Niino M, Tanaka A, Shirai F, Shirouzu M, Koyama H, Honma T..  (2017)  Activity cliff for 7-substituted pyrrolo-pyrimidine inhibitors of HCK explained in terms of predicted basicity of the amine nitrogen.,  25  (16): [PMID:28662963] [10.1016/j.bmc.2017.05.053]

2. Koda Y, Kikuzato K, Mikuni J, Tanaka A, Yuki H, Honma T, Tomabechi Y, Kukimoto-Niino M, Shirouzu M, Shirai F, Koyama H..  (2017)  Identification of pyrrolo[2,3-d]pyrimidines as potent HCK and FLT3-ITD dual inhibitors.,  27  (22): [PMID:29037944] [10.1016/j.bmcl.2017.10.012]

3. Das, Jagabandhu J and 20 more authors.  2006-11-16  2-aminothiazole as a novel kinase inhibitor template. Structure-activity relationship studies toward the discovery of N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1- piperazinyl)]-2-methyl-4-pyrimidinyl]amino)]-1,3-thiazole-5-carboxamide (dasatinib, BMS-354825) as a potent pan-Src kinase inhibitor.  [PMID:17154512]

4. Apsel, Beth and 9 more authors.  2008-11  Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases.  [PMID:18849971]

5. Remsing Rix, L L LL and 11 more authors.  2009-03  Global target profile of the kinase inhibitor bosutinib in primary chronic myeloid leukemia cells.  [PMID:19039322]

6. Byrd, John C JC and 29 more authors.  2016-01-28  Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia.  [PMID:26641137]

7. Daydé-Cazals, Bénédicte B and 11 more authors.  2016-04-28  Rational Design, Synthesis, and Biological Evaluation of 7-Azaindole Derivatives as Potent Focused Multi-Targeted Kinase Inhibitors.  [PMID:27010810]

8. Fraser, Craig C and 13 more authors.  2016-05-26  Rapid Discovery and Structure-Activity Relationships of Pyrazolopyrimidines That Potently Suppress Breast Cancer Cell Growth via SRC Kinase Inhibition with Exceptional Selectivity over ABL Kinase.  [PMID:27115835]

9. Bachegowda, Lohith L and 35 more authors.  2016-08-15  Pexmetinib: A Novel Dual Inhibitor of Tie2 and p38 MAPK with Efficacy in Preclinical Models of Myelodysplastic Syndromes and Acute Myeloid Leukemia.  [PMID:27287719]

10. Zhang, Chun-Hui CH and 17 more authors.  2016-11-10  From Lead to Drug Candidate: Optimization of 3-(Phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine Derivatives as Agents for the Treatment of Triple Negative Breast Cancer.  [PMID:27739679]

11. Yuki, Hitomi H and 10 more authors.  2017-08-15  Activity cliff for 7-substituted pyrrolo-pyrimidine inhibitors of HCK explained in terms of predicted basicity of the amine nitrogen.  [PMID:28662963]

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

13. He, Linhong L and 9 more authors.  2018-02-10  Design, synthesis and biological evaluation of 7H-pyrrolo[2,3-d]pyrimidin-4-amine derivatives as selective Btk inhibitors with improved pharmacokinetic properties for the treatment of rheumatoid arthritis.  [PMID:29324347]

14. Dart, Melanie L and 11 more authors.  2018-06-14  Homogeneous Assay for Target Engagement Utilizing Bioluminescent Thermal Shift.  [PMID:29937980]

15. 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]

Source

Source(1):

• Scientific Literature