(S)-5-(2-methoxyethyl)-6-methyl-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one

ID: ALA4087393

PubChem CID: 126480564

Max Phase: Preclinical

Molecular Formula: C20H25N7O2

Molecular Weight: 395.47

Molecule Type: Small molecule

Names and Identifiers

Canonical SMILES:  COCCN1C(=O)c2cc(-c3nc(Nc4ccnn4C)ncc3C)[nH]c2C[C@@H]1C

Standard InChI:  InChI=1S/C20H25N7O2/c1-12-11-21-20(24-17-5-6-22-26(17)3)25-18(12)16-10-14-15(23-16)9-13(2)27(19(14)28)7-8-29-4/h5-6,10-11,13,23H,7-9H2,1-4H3,(H,21,24,25)/t13-/m0/s1

Standard InChI Key:  PNXHDOWDWLRBSB-ZDUSSCGKSA-N

Molfile:  

     RDKit          2D

 29 32  0  0  0  0  0  0  0  0999 V2000
   10.0256   -9.2464    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   10.7347   -8.8378    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   10.7347   -8.0206    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   10.0256   -7.6120    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    9.3206   -8.0206    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    9.3206   -8.8378    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   11.5119   -7.7701    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   11.5119   -9.0925    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   11.9921   -8.4292    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   10.0256  -10.0636    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
   14.0350   -7.7243    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   13.2179   -7.7243    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   12.8093   -8.4292    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   13.2179   -9.1383    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   14.0350   -9.1383    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   14.4436   -8.4292    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   14.4436   -7.0152    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   15.7451   -7.6743    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   16.5182   -7.4238    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   16.5182   -6.6066    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   15.7451   -6.3519    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   15.2608   -7.0152    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   15.4904   -8.4516    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   12.8093   -9.8474    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    8.6116   -7.6120    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    8.6116   -9.2464    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    7.9066   -8.8378    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    7.9066   -8.0206    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
    7.1975   -7.6121    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  1  0
  5  6  1  0
  1  6  1  0
  8  9  2  0
  7  9  1  0
  2  8  1  0
  3  7  1  0
  1 10  2  0
 11 12  1  0
 12 13  2  0
 13 14  1  0
 14 15  2  0
 15 16  1  0
 11 16  2  0
 18 19  1  0
 19 20  2  0
 20 21  1  0
 21 22  2  0
 18 22  1  0
 18 23  1  0
 17 22  1  0
 11 17  1  0
 14 24  1  0
  9 13  1  0
  5 25  1  1
 26 27  1  0
 28 29  1  0
 27 28  1  0
  6 26  1  0
M  END

Alternative Forms

1. Parent:

   

   ALA4087393

   ---

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: 395.47

Molecular Weight (Monoisotopic): 395.2070

AlogP: 2.29

#Rotatable Bonds: 6

Polar Surface Area: 100.96

Molecular Species: NEUTRAL

HBA: 7

HBD: 2

#RO5 Violations: ┄

HBA (Lipinski): 9

HBD (Lipinski): 2

#RO5 Violations (Lipinski): ┄

CX Acidic pKa: 12.32

CX Basic pKa: 3.06

CX LogP: 1.63

CX LogD: 1.63

Aromatic Rings: 3

Heavy Atoms: 29

QED Weighted: 0.66

Np Likeness Score: -1.46

References

1. Ward RA, Bethel P, Cook C, Davies E, Debreczeni JE, Fairley G, Feron L, Flemington V, Graham MA, Greenwood R, Griffin N, Hanson L, Hopcroft P, Howard TD, Hudson J, James M, Jones CD, Jones CR, Lamont S, Lewis R, Lindsay N, Roberts K, Simpson I, St-Gallay S, Swallow S, Tang J, Tonge M, Wang Z, Zhai B..  (2017)  Structure-Guided Discovery of Potent and Selective Inhibitors of ERK1/2 from a Modestly Active and Promiscuous Chemical Start Point.,  60  (8): [PMID:28376306] [10.1021/acs.jmedchem.7b00267]

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