2-{4-[(2-Methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl)-prop-2-ynyl-amino]-benzoylamino}-pentanedioic acid

ID: ALA434209

PubChem CID: 135400203

Max Phase: Preclinical

Molecular Formula: C25H24N4O6

Molecular Weight: 476.49

Molecule Type: Small molecule

Names and Identifiers

Canonical SMILES:  C#CCN(Cc1ccc2nc(C)[nH]c(=O)c2c1)c1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1

Standard InChI:  InChI=1S/C25H24N4O6/c1-3-12-29(14-16-4-9-20-19(13-16)24(33)27-15(2)26-20)18-7-5-17(6-8-18)23(32)28-21(25(34)35)10-11-22(30)31/h1,4-9,13,21H,10-12,14H2,2H3,(H,28,32)(H,30,31)(H,34,35)(H,26,27,33)/t21-/m0/s1

Standard InChI Key:  PMTUUSDTAKQWQJ-NRFANRHFSA-N

Molfile:  

     RDKit          2D

 35 37  0  0  0  0  0  0  0  0999 V2000
   -4.0875   -1.3042    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   -4.0875   -2.1292    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -3.3755   -2.5375    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   -3.3755   -0.8875    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -4.8014   -2.5427    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -3.3755   -0.0625    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
   -2.6635   -1.3042    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -2.6651   -2.1273    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -1.9541   -2.5385    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -1.2411   -2.1277    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -1.2435   -1.3014    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -1.9550   -0.8939    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -0.5303   -0.8866    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    0.1855   -1.2968    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    0.8986   -0.8820    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    0.1881   -2.1218    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    1.6158   -1.2946    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    2.3285   -0.8805    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    2.3263   -0.0547    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    1.6055    0.3554    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    0.8957   -0.0611    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    3.0389    0.3611    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    3.0351    1.1861    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
    3.7516   -0.0456    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    4.4640    0.3705    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    5.1805   -0.0384    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    4.4598    1.1955    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    5.1720    1.6120    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
    3.7430    1.6048    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
    5.8929    0.3777    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    6.6095   -0.0312    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    6.6146   -0.8575    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
    7.3228    0.3836    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
    0.9039   -2.5320    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    1.6125   -2.9417    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
 15 17  2  0
  3  8  1  0
 17 18  1  0
  8  9  1  0
 18 19  2  0
  7  4  1  0
 19 20  1  0
  9 10  2  0
 20 21  2  0
 21 15  1  0
 19 22  1  0
 10 11  1  0
 22 23  2  0
  2  5  1  0
 22 24  1  0
 11 12  2  0
 24 25  1  0
 12  7  1  0
 25 26  1  6
  1  2  1  0
 25 27  1  0
 11 13  1  0
  4  6  2  0
 27 28  1  0
 27 29  2  0
 13 14  1  0
 26 30  1  0
  1  4  1  0
 30 31  1  0
 14 15  1  0
  2  3  2  0
 31 32  1  0
 31 33  2  0
 14 16  1  0
 16 34  1  0
  7  8  2  0
 34 35  3  0
M  END

Alternative Forms

1. Parent:

   

   ALA434209

   ---

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: 476.49

Molecular Weight (Monoisotopic): 476.1696

AlogP: 1.92

#Rotatable Bonds: 10

Polar Surface Area: 152.69

Molecular Species: ACID

HBA: 6

HBD: 4

#RO5 Violations: ┄

HBA (Lipinski): 10

HBD (Lipinski): 4

#RO5 Violations (Lipinski): ┄

CX Acidic pKa: 3.24

CX Basic pKa: 6.10

CX LogP: 0.44

CX LogD: -3.59

Aromatic Rings: 3

Heavy Atoms: 35

QED Weighted: 0.32

Np Likeness Score: -0.97

References

1. Marsham PR, Hughes LR, Jackman AL, Hayter AJ, Oldfield J, Wardleworth JM, Bishop JA, O'Connor BM, Calvert AH..  (1991)  Quinazoline antifolate thymidylate synthase inhibitors: heterocyclic benzoyl ring modifications.,  34  (5): [PMID:2033585] [10.1021/jm00109a011]

2. Marsham PR, Jackman AL, Hayter AJ, Daw MR, Snowden JL, O'Connor BM, Bishop JA, Calvert AH, Hughes LR..  (1991)  Quinazoline antifolate thymidylate synthase inhibitors: bridge modifications and conformationally restricted analogues in the C2-methyl series.,  34  (7): [PMID:2066994] [10.1021/jm00111a042]

3. Thornton TJ, Jackman AL, Marsham PR, O'Connor BM, Bishop JA, Calvert AH..  (1992)  Quinazoline antifolate thymidylate synthase inhibitors: difluoro-substituted benzene ring analogues.,  35  (12): [PMID:1613755] [10.1021/jm00090a024]

4. Hughes LR, Jackman AL, Oldfield J, Smith RC, Burrows KD, Marsham PR, Bishop JA, Jones TR, O'Connor BM, Calvert AH..  (1990)  Quinazoline antifolate thymidylate synthase inhibitors: alkyl, substituted alkyl, and aryl substituents in the C2 position.,  33  (11): [PMID:2231606] [10.1021/jm00173a024]

5. Jackman AL, Marsham PR, Thornton TJ, Bishop JA, O'Connor BM, Hughes LR, Calvert AH, Jones TR..  (1990)  Quinazoline antifolate thymidylate synthase inhibitors: 2'-fluoro-N10-propargyl-5,8-dideazafolic acid and derivatives with modifications in the C2 position.,  33  (11): [PMID:2231607] [10.1021/jm00173a025]

6. Marsham PR, Jackman AL, Oldfield J, Hughes LR, Thornton TJ, Bisset GM, O'Connor BM, Bishop JA, Calvert AH..  (1990)  Quinazoline antifolate thymidylate synthase inhibitors: benzoyl ring modifications in the C2-methyl series.,  33  (11): [PMID:2231608] [10.1021/jm00173a026]

7. Pendergast W, Dickerson SH, Johnson JV, Dev IK, Ferone R, Duch DS, Smith GK..  (1993)  Benzoquinazoline inhibitors of thymidylate synthase: enzyme inhibitory activity and cytotoxicity of some sulfonamidobenzoylglutamate and related derivatives.,  36  (22): [PMID:8230138] [10.1021/jm00074a030]

8. Marsham PR, Wardleworth JM, Boyle FT, Hennequin LF, Kimbell R, Brown M, Jackman AL..  (1999)  Design and synthesis of potent non-polyglutamatable quinazoline antifolate thymidylate synthase inhibitors.,  42  (19): [PMID:10508430] [10.1021/jm9803727]

9. Bisset GM, Pawelczak K, Jackman AL, Calvert AH, Hughes LR..  (1992)  Syntheses and thymidylate synthase inhibitory activity of the poly-gamma-glutamyl conjugates of N-[5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino ]-2-thenoyl]-L-glutamic acid (ICI D1694) and other quinazoline antifolates.,  35  (5): [PMID:1372358] [10.1021/jm00083a008]

10. Srivastava V, Gupta SP, Siddiqi MI, Mishra BN..  (2010)  3D-QSAR studies on quinazoline antifolate thymidylate synthase inhibitors by CoMFA and CoMSIA models.,  45  (4): [PMID:20153089] [10.1016/j.ejmech.2009.12.065]

Source

Source(1):

• Scientific Literature