US9206139, 4

ID: ALA3955404

PubChem CID: 74221131

Max Phase: Preclinical

Molecular Formula: C20H24F3N3O3

Molecular Weight: 411.42

Molecule Type: Small molecule

Names and Identifiers

Canonical SMILES:  CC(C)[C@H](Cc1ccc(C(F)(F)F)cc1)C(=O)NC[C@@]1(C2CC2)NC(=O)NC1=O

Standard InChI:  InChI=1S/C20H24F3N3O3/c1-11(2)15(9-12-3-5-14(6-4-12)20(21,22)23)16(27)24-10-19(13-7-8-13)17(28)25-18(29)26-19/h3-6,11,13,15H,7-10H2,1-2H3,(H,24,27)(H2,25,26,28,29)/t15-,19-/m0/s1

Standard InChI Key:  VXXYNKXMRXANKX-KXBFYZLASA-N

Molfile:  

     RDKit          2D

 29 31  0  0  1  0  0  0  0  0999 V2000
    0.2552   -3.1461    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    1.2925   -3.7494    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    1.2883   -4.9494    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    2.5951   -3.0039    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    2.5973   -1.5031    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
   -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
   -2.5988    1.5004    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   -2.5996    2.7004    0.0000 F   0  0  0  0  0  0  0  0  0  0  0  0
   -3.6378    0.9001    0.0000 F   0  0  0  0  0  0  0  0  0  0  0  0
   -3.6383    2.0999    0.0000 F   0  0  0  0  0  0  0  0  0  0  0  0
    3.8933   -3.7570    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    4.9336   -3.1588    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
    3.8912   -5.2578    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    5.1894   -6.0109    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    5.1873   -7.5117    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    3.8731   -6.8677    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    2.8676   -7.9808    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    1.6744   -7.8535    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
    3.6156   -9.2811    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
    5.0833   -8.9715    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    5.9878   -9.7601    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
    6.4861   -8.2646    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    7.1546   -9.5191    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    7.9069   -8.2213    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
  1  2  1  0
  2  3  1  0
  2  4  1  0
  4  5  1  6
  5  6  1  0
  6  7  2  0
  7  8  1  0
  8  9  2  0
  9 10  1  0
 10 11  2  0
 11  6  1  0
  9 12  1  0
 12 13  1  0
 12 14  1  0
 12 15  1  0
  4 16  1  0
 16 17  2  0
 16 18  1  0
 18 19  1  0
 20 19  1  6
 20 21  1  0
 21 22  1  0
 22 23  2  0
 22 24  1  0
 24 25  1  0
 25 20  1  0
 25 26  2  0
 20 27  1  0
 27 28  1  0
 28 29  1  0
 29 27  1  0
M  END

Alternative Forms

1. Parent:

   

   ALA3955404

   (2S)-N-[[(4R)-4-cyclopropyl-2,5-dioxoimidazolidin-4-yl]methyl]-3-methyl-2-[[4-(trifluoromethyl)phenyl]methyl]butanamide

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: 411.42

Molecular Weight (Monoisotopic): 411.1770

AlogP: 2.62

#Rotatable Bonds: 7

Polar Surface Area: 87.30

Molecular Species: NEUTRAL

HBA: 3

HBD: 3

#RO5 Violations: ┄

HBA (Lipinski): 6

HBD (Lipinski): 3

#RO5 Violations (Lipinski): ┄

CX Acidic pKa: 8.88

CX Basic pKa: ┄

CX LogP: 3.07

CX LogD: 3.06

Aromatic Rings: 1

Heavy Atoms: 29

QED Weighted: 0.60

Np Likeness Score: -0.38

References

1.  (2015)  Aggrecanase inhibitors, 

2. Durham TB, Marimuthu J, Toth JL, Liu C, Adams L, Mudra DR, Swearingen C, Lin C, Chambers MG, Thirunavukkarasu K, Wiley MR..  (2017)  A Highly Selective Hydantoin Inhibitor of Aggrecanase-1 and Aggrecanase-2 with a Low Projected Human Dose.,  60  (13): [PMID:28613895] [10.1021/acs.jmedchem.7b00650]

3. Xiang, Jason S JS and 12 more authors.  2006-01-15  Synthesis and biological evaluation of biphenylsulfonamide carboxylate aggrecanase-1 inhibitors.  [PMID:16275085]

4. Hopper, Darrin W DW and 17 more authors.  2009-05-01  Synthesis and biological evaluation of ((4-keto)-phenoxy)methyl biphenyl-4-sulfonamides: a class of potent aggrecanase-1 inhibitors.  [PMID:19329309]

5. De Savi, Chris C and 13 more authors.  2011-03-01  The design and synthesis of novel N-hydroxyformamide inhibitors of ADAM-TS4 for the treatment of osteoarthritis.  [PMID:21300546]

6. Shiozaki, Makoto M and 24 more authors.  2011-04-28  Discovery of (1S,2R,3R)-2,3-dimethyl-2-phenyl-1-sulfamidocyclopropanecarboxylates: novel and highly selective aggrecanase inhibitors.  [PMID:21417219]

7. De Savi, Chris C and 11 more authors.  2011-06-01  Orally active achiral N-hydroxyformamide inhibitors of ADAM-TS4 (aggrecanase-1) and ADAM-TS5 (aggrecanase-2) for the treatment of osteoarthritis.  [PMID:21536437]

8. Deng, Hongfeng H and 24 more authors.  2012-08-23  Discovery of highly potent and selective small molecule ADAMTS-5 inhibitors that inhibit human cartilage degradation via encoded library technology (ELT).  [PMID:22891645]

9. Nuti, Elisa E and 14 more authors.  2013-04  Arylsulfonamide inhibitors of aggrecanases as potential therapeutic agents for osteoarthritis: synthesis and biological evaluation.  [PMID:23376997]

10. Maingot, Lucie L and 12 more authors.  2013-11  Aggrecanase-2 inhibitors based on the acylthiosemicarbazide zinc-binding group.  [PMID:24044937]

11. Durham, Timothy B TB and 13 more authors.  2014-12-26  Identification of potent and selective hydantoin inhibitors of aggrecanase-1 and aggrecanase-2 that are efficacious in both chemical and surgical models of osteoarthritis.  [PMID:25415648]

12. Ding, Yun Y and 13 more authors.  2015-08-13  Discovery of Potent and Selective Inhibitors for ADAMTS-4 through DNA-Encoded Library Technology (ELT).  [PMID:26288689]

13. Durham, Timothy B TB and 10 more authors.  2017-07-13  A Highly Selective Hydantoin Inhibitor of Aggrecanase-1 and Aggrecanase-2 with a Low Projected Human Dose.  [PMID:28613895]

Source

Source(2):

• Scientific Literature
• BindingDB Database