7-(5-Methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-2-((6-methylpyridin-2-yl)methyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one

ID: ALA4101072

PubChem CID: 122604256

Max Phase: Preclinical

Molecular Formula: C23H24N8O

Molecular Weight: 428.50

Molecule Type: Small molecule

Names and Identifiers

Canonical SMILES:  Cc1cccc(CN2CCn3cc(-c4nc(Nc5ccnn5C)ncc4C)cc3C2=O)n1

Standard InChI:  InChI=1S/C23H24N8O/c1-15-12-24-23(27-20-7-8-25-29(20)3)28-21(15)17-11-19-22(32)31(10-9-30(19)13-17)14-18-6-4-5-16(2)26-18/h4-8,11-13H,9-10,14H2,1-3H3,(H,24,27,28)

Standard InChI Key:  KZNKCUQAIPNSJI-UHFFFAOYSA-N

Molfile:  

     RDKit          2D

 32 36  0  0  0  0  0  0  0  0999 V2000
   12.3881   -8.9154    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   13.1033   -9.3275    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   12.3881   -8.0911    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   13.8185   -8.9154    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   13.8185   -8.0911    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   13.1033   -7.6790    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   11.6040   -9.1723    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   11.1197   -8.5033    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   11.6040   -7.8383    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   13.1033  -10.1518    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
   14.5297   -9.3275    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   15.2449   -8.9154    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   15.2449   -8.0911    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   15.9602   -7.6790    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   16.6713   -8.0911    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   16.6713   -8.9154    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   15.9602   -9.3275    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   17.3866   -9.3275    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    9.0589   -7.7921    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    9.8832   -7.7921    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   10.2954   -8.5033    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    9.8832   -9.2185    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    9.0589   -9.2185    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    8.6467   -8.5033    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    8.6467   -7.0769    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    7.3381   -7.7417    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    6.5541   -7.4890    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    6.5541   -6.6647    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    7.3381   -6.4078    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    7.8224   -7.0769    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    7.5950   -8.5258    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   10.2954   -9.9296    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
  1  2  1  0
  1  3  1  0
  2  4  1  0
  4  5  1  0
  5  6  1  0
  3  6  1  0
  7  8  1  0
  8  9  2  0
  3  9  1  0
  1  7  2  0
  2 10  2  0
 12 13  1  0
 13 14  2  0
 14 15  1  0
 15 16  2  0
 16 17  1  0
 12 17  2  0
 16 18  1  0
 11 12  1  0
  4 11  1  0
 19 20  1  0
 20 21  2  0
 21 22  1  0
 22 23  2  0
 23 24  1  0
 19 24  2  0
 26 27  1  0
 27 28  2  0
 28 29  1  0
 29 30  2  0
 26 30  1  0
 26 31  1  0
 25 30  1  0
 19 25  1  0
 22 32  1  0
  8 21  1  0
M  END

Alternative Forms

1. Parent:

   

   ALA4101072

   ---

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: 428.50

Molecular Weight (Monoisotopic): 428.2073

AlogP: 3.09

#Rotatable Bonds: 5

Polar Surface Area: 93.76

Molecular Species: NEUTRAL

HBA: 8

HBD: 1

#RO5 Violations: ┄

HBA (Lipinski): 9

HBD (Lipinski): 1

#RO5 Violations (Lipinski): ┄

CX Acidic pKa: 12.78

CX Basic pKa: 4.85

CX LogP: 2.30

CX LogD: 2.30

Aromatic Rings: 4

Heavy Atoms: 32

QED Weighted: 0.53

Np Likeness Score: -1.71

References

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2. 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]

3. Goto, Masaki M and 14 more authors.  2009-11  E6201 [(3S,4R,5Z,8S,9S,11E)-14-(ethylamino)-8, 9,16-trihydroxy-3,4-dimethyl-3,4,9,19-tetrahydro-1H-2-benzoxacyclotetradecine-1,7(8H)-dione], a novel kinase inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK)-1 and MEK kinase-1: in vitro characterization of its anti-inflammatory and antihyperproliferative activities.  [PMID:19684251]

4. Daouti, Sherif S and 15 more authors.  2010-01  Preclinical in vivo evaluation of efficacy, pharmacokinetics, and pharmacodynamics of a novel MEK1/2 kinase inhibitor RO5068760 in multiple tumor models.  [PMID:20053779]

5. Kim, Mi-hyun MH and 6 more authors.  2011-03-15  Structure based design and syntheses of amino-1H-pyrazole amide derivatives as selective Raf kinase inhibitors in melanoma cells.  [PMID:21353571]

6. Kim, Hyangmi; Kim, Minjung; Lee, Junghun; Yu, Hana and Hah, Jung-Mi.  2011-11-15  Syntheses of phenylpyrazolodiazepin-7-ones as conformationally rigid analogs of aminopyrazole amide scaffold and their antiproliferative effects on cancer cells.  [PMID:22014755]

7. Wang, Yuanxiang Y, Kaiser, Christine E CE, Frett, Brendan B and Li, Hong-Yu HY.  2013-07-11  Targeting mutant KRAS for anticancer therapeutics: a review of novel small molecule modulators.  [PMID:23566315]

8. Hatzivassiliou, Georgia G and 20 more authors.  2013-09-12  Mechanism of MEK inhibition determines efficacy in mutant KRAS- versus BRAF-driven cancers.  [PMID:23934108]

9. Aoki, Toshihiro T and 18 more authors.  2014-04-10  Optimizing the Physicochemical Properties of Raf/MEK Inhibitors by Nitrogen Scanning.  [PMID:24900832]

10. Van Dort, Marcian E and 7 more authors.  2015-04-01  Dual inhibition of allosteric mitogen-activated protein kinase (MEK) and phosphatidylinositol 3-kinase (PI3K) oncogenic targets with a bifunctional inhibitor.  [PMID:25766633]

11. Van Dort, Marcian E and 7 more authors.  2016-03-24  Discovery of Bifunctional Oncogenic Target Inhibitors against Allosteric Mitogen-Activated Protein Kinase (MEK1) and Phosphatidylinositol 3-Kinase (PI3K).  [PMID:26943489]

12. Tan, Li and 15 more authors.  2017-02-01  Structure-guided development of covalent TAK1 inhibitors.  [PMID:28011204]

13. Wu, Wei W and 12 more authors.  2017-02-01  Macrocyclic MEK1/2 inhibitor with efficacy in a mouse model of cardiomyopathy caused by lamin A/C gene mutation.  [PMID:28011205]

14. Van Dort, Marcian E ME and 9 more authors.  2017-08-10  Structure-Guided Design and Initial Studies of a Bifunctional MEK/PI3K Inhibitor (ST-168).  [PMID:28835793]

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

16. 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