(E)-2-(3-(3,4-bis(benzyloxy)phenyl)acryloyloxy)-3-(3,4-dimethoxyphenyl)propanoic acid

ID: ALA2333273

PubChem CID: 71652361

Max Phase: Preclinical

Molecular Formula: C34H32O8

Molecular Weight: 568.62

Molecule Type: Small molecule

Names and Identifiers

Canonical SMILES:  COc1ccc(CC(OC(=O)/C=C/c2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)C(=O)O)cc1OC

Standard InChI:  InChI=1S/C34H32O8/c1-38-28-16-14-27(20-30(28)39-2)21-32(34(36)37)42-33(35)18-15-24-13-17-29(40-22-25-9-5-3-6-10-25)31(19-24)41-23-26-11-7-4-8-12-26/h3-20,32H,21-23H2,1-2H3,(H,36,37)/b18-15+

Standard InChI Key:  HTYCVVAAKRVDGM-OBGWFSINSA-N

Molfile:  

     RDKit          2D

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    7.3644   -4.2511    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    4.5012   -2.6132    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
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    8.7940   -4.2469    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
    5.9265   -1.7838    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
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    1.6421   -2.6215    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
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    1.6504   -4.2719    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
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    1.6515   -5.0972    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   10.2216   -2.5970    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
   10.2216   -4.2465    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
   10.9359   -3.0100    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
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   13.0729   -4.2449    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   12.3589   -3.8355    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
  2  1  1  0
  3  4  1  0
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  6 12  1  0
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  6 10  2  0
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 39 40  2  0
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 42 32  1  0
M  END

Alternative Forms

1. Parent:

   

   ALA2333273

   2-[(E)-3-[3,4-bis(phenylmethoxy)phenyl]prop-2-enoyl]oxy-3-(3,4-dimethoxyphenyl)propanoic 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: 568.62

Molecular Weight (Monoisotopic): 568.2097

AlogP: 6.11

#Rotatable Bonds: 14

Polar Surface Area: 100.52

Molecular Species: ACID

HBA: 7

HBD: 1

#RO5 Violations: 2

HBA (Lipinski): 8

HBD (Lipinski): 1

#RO5 Violations (Lipinski): 2

CX Acidic pKa: 3.25

CX Basic pKa: ┄

CX LogP: 7.04

CX LogD: 3.60

Aromatic Rings: 4

Heavy Atoms: 42

QED Weighted: 0.14

Np Likeness Score: 0.33

References

1. Yuan H, Lu W, Wang L, Shan L, Li H, Huang J, Sun Q, Zhang W..  (2013)  Synthesis of derivatives of methyl rosmarinate and their inhibitory activities against matrix metalloproteinase-1 (MMP-1).,  62  [PMID:23353736] [10.1016/j.ejmech.2012.09.047]

2. Cheng, M M and 13 more authors.  1999-12-30  Design, synthesis, and biological evaluation of matrix metalloproteinase inhibitors derived from a modified proline scaffold.  [PMID:10639284]

3. Cheng, M M and 15 more authors.  2000-02-10  Design and synthesis of piperazine-based matrix metalloproteinase inhibitors.  [PMID:10669564]

4. Natchus, M G MG and 17 more authors.  2001-03-29  Development of new carboxylic acid-based MMP inhibitors derived from functionalized propargylglycines.  [PMID:11297453]

5. Levin, J I JI and 23 more authors.  2003-08-18  Acetylenic TACE inhibitors. Part 1. SAR of the acyclic sulfonamide hydroxamates.  [PMID:12873518]

6. Zask, Arie A and 12 more authors.  2005-03-15  Synthesis and SAR of diazepine and thiazepine TACE and MMP inhibitors.  [PMID:15745814]

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

8. Johnson, Adam R AR and 17 more authors.  2007-09-21  Discovery and characterization of a novel inhibitor of matrix metalloprotease-13 that reduces cartilage damage in vivo without joint fibroplasia side effects.  [PMID:17623656]

9. Zhang, Yue-Mei YM and 10 more authors.  2008-01-01  1-Hydroxy-2-pyridinone-based MMP inhibitors: synthesis and biological evaluation for the treatment of ischemic stroke.  [PMID:17981034]

10. Yang, Shyh-Ming SM and 9 more authors.  2008-02-01  beta-N-Biaryl ether sulfonamide hydroxamates as potent gelatinase inhibitors: part 2. Optimization of alpha-amino substituents.  [PMID:18083558]

11. Li, Jie Jack JJ and 11 more authors.  2008-02-28  Quinazolinones and pyrido[3,4-d]pyrimidin-4-ones as orally active and specific matrix metalloproteinase-13 inhibitors for the treatment of osteoarthritis.  [PMID:18251495]

12. Lauer-Fields, Janelle L JL and 7 more authors.  2009-02-01  High throughput screening of potentially selective MMP-13 exosite inhibitors utilizing a triple-helical FRET substrate.  [PMID:18358729]

13. Georgiadis, Dimitris D and Yiotakis, Athanasios A.  2008-10-01  Specific targeting of metzincin family members with small-molecule inhibitors: progress toward a multifarious challenge.  [PMID:18790648]

14. DasGupta, Shirshendu S, Murumkar, Prashant R PR, Giridhar, Rajani R and Yadav, Mange Ram MR.  2009-01-15  Current perspective of TACE inhibitors: a review.  [PMID:19095454]

15. Li, Wei W and 15 more authors.  2009-04-09  A selective matrix metalloprotease 12 inhibitor for potential treatment of chronic obstructive pulmonary disease (COPD): discovery of (S)-2-(8-(methoxycarbonylamino)dibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoic acid (MMP408).  [PMID:19278250]

16. 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]

17. Monovich, Lauren G LG and 35 more authors.  2009-06-11  Discovery of potent, selective, and orally active carboxylic acid based inhibitors of matrix metalloproteinase-13.  [PMID:19422229]

18. Nuti, Elisa E and 15 more authors.  2009-08-13  N-O-isopropyl sulfonamido-based hydroxamates: design, synthesis and biological evaluation of selective matrix metalloproteinase-13 inhibitors as potential therapeutic agents for osteoarthritis.  [PMID:19606871]

19. Li, Wei W and 19 more authors.  2009-09-10  Identification of an orally efficacious matrix metalloprotease 12 inhibitor for potential treatment of asthma.  [PMID:19725580]

20. Nuti, Elisa E and 13 more authors.  2009-10-22  Design, synthesis, biological evaluation, and NMR studies of a new series of arylsulfones as selective and potent matrix metalloproteinase-12 inhibitors.  [PMID:19775099]

21. Schnute, Mark E ME and 29 more authors.  2010-01-15  Discovery of (pyridin-4-yl)-2H-tetrazole as a novel scaffold to identify highly selective matrix metalloproteinase-13 inhibitors for the treatment of osteoarthritis.  [PMID:20005097]

22. 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]

23. 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]

24. 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]

25. Tommasi, Ruben A RA and 20 more authors.  2011-11-01  Potent and selective 2-naphthylsulfonamide substituted hydroxamic acid inhibitors of matrix metalloproteinase-13.  [PMID:21937229]

26. Taylor, Steven J SJ and 18 more authors.  2011-12-08  Fragment-based discovery of indole inhibitors of matrix metalloproteinase-13.  [PMID:22017539]

27. Roth, Joshua J and 7 more authors.  2011-12-01  Identification of novel, exosite-binding matrix metalloproteinase-13 inhibitor scaffolds.  [PMID:22018790]

28. De Savi, Chris C and 6 more authors.  2012-01-01  Lead optimisation of selective non-zinc binding inhibitors of MMP13. Part 2.  [PMID:22153941]

29. Gege, Christian C and 9 more authors.  2012-01-26  Discovery and evaluation of a non-Zn chelating, selective matrix metalloproteinase 13 (MMP-13) inhibitor for potential intra-articular treatment of osteoarthritis.  [PMID:22175799]

30. 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]

31. 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]

32. Jin, Yonghao Y and 6 more authors.  2013-06-13  Matrix metalloproteinase inhibitors based on the 3-mercaptopyrrolidine core.  [PMID:23631440]

33. Nara, Hiroshi H and 11 more authors.  2014-11-13  Discovery of novel, highly potent, and selective quinazoline-2-carboxamide-based matrix metalloproteinase (MMP)-13 inhibitors without a zinc binding group using a structure-based design approach.  [PMID:25264600]

34. Spicer, Timothy P TP and 8 more authors.  2014-11-26  Characterization of selective exosite-binding inhibitors of matrix metalloproteinase 13 that prevent articular cartilage degradation in vitro.  [PMID:25330343]

35. 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]

36. Crascì, Lucia L and 5 more authors.  2015-04-01  2-Benzisothiazolylimino-5-benzylidene-4-thiazolidinones as protective agents against cartilage destruction.  [PMID:25725607]

37. Ruminski, Peter G PG and 25 more authors.  2016-01-14  Discovery of N-(4-Fluoro-3-methoxybenzyl)-6-(2-(((2S,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide. A Highly Selective and Orally Bioavailable Matrix Metalloproteinase-13 Inhibitor for the Potential Treatment of Osteoarthritis.  [PMID:26653735]

38. Nara, Hiroshi H and 9 more authors.  2016-12-01  Design, synthesis, and biological activity of novel, potent, and highly selective fused pyrimidine-2-carboxamide-4-one-based matrix metalloproteinase (MMP)-13 zinc-binding inhibitors.  [PMID:27825552]

39. Ramsbeck, Daniel D, Hamann, Antje A, Schlenzig, Dagmar D, Schilling, Stephan S and Buchholz, Mirko M.  2017-06-01  First insight into structure-activity relationships of selective meprin β inhibitors.  [PMID:28408220]

40. 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]

41. Choi, Jun Yong and 8 more authors.  2017-07-13  Structure-Based Design and Synthesis of Potent and Selective Matrix Metalloproteinase 13 Inhibitors.  [PMID:28653849]

42. Senn, Nicole N, Ott, Michael M, Lanz, Jan J and Riedl, Rainer R.  2017-12-14  Targeted Polypharmacology: Discovery of a Highly Potent Non-Hydroxamate Dual Matrix Metalloproteinase (MMP)-10/-13 Inhibitor.  [PMID:28953404]

43. Hagimori, Masayori M and 5 more authors.  2018-01-15  Synthesis of radioiodinated probes targeted toward matrix metalloproteinase-12.  [PMID:29191557]

44. Fuerst, Rita and 7 more authors.  2018-10-01  Development of matrix metalloproteinase-13 inhibitors - A structure-activity/structure-property relationship study.  [PMID:30249495]

45. Gona, Kiran and 12 more authors.  2020-12-10  Hydroxamate-Based Selective Macrophage Elastase (MMP-12) Inhibitors and Radiotracers for Molecular Imaging.  [PMID:33206510]

Source

Source(1):

• Scientific Literature