(3S,7S,8S)-7-Hydroxy-3-isopropyl-8-(thiazol-4-ylmethyl)-1,4,9-triazacyclohenicosane-2,5,10-trione

ID: ALA4451023

PubChem CID: 155522348

Max Phase: Preclinical

Molecular Formula: C25H42N4O4S

Molecular Weight: 494.70

Molecule Type: Unknown

Names and Identifiers

Canonical SMILES:  CC(C)[C@@H]1NC(=O)C[C@H](O)[C@H](Cc2cscn2)NC(=O)CCCCCCCCCCCNC1=O

Standard InChI:  InChI=1S/C25H42N4O4S/c1-18(2)24-25(33)26-13-11-9-7-5-3-4-6-8-10-12-22(31)28-20(14-19-16-34-17-27-19)21(30)15-23(32)29-24/h16-18,20-21,24,30H,3-15H2,1-2H3,(H,26,33)(H,28,31)(H,29,32)/t20-,21-,24-/m0/s1

Standard InChI Key:  MLHYCOZSDSMTFO-HFMPRLQTSA-N

Molfile:  

 
     RDKit          2D

 34 35  0  0  0  0  0  0  0  0999 V2000
   17.1940  -13.1617    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   17.8811  -12.7655    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   18.5723  -13.1617    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   19.2594  -12.7655    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   19.9465  -13.1617    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   20.6294  -12.7655    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   21.3165  -13.1617    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   21.3165  -13.9542    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   17.1940  -13.9542    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   21.9994  -14.3504    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   21.9994  -15.2584    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   16.5070  -14.3504    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   16.5070  -15.1428    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   15.8199  -15.5431    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
   17.1940  -15.5431    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   17.1940  -16.3356    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   17.8811  -16.7318    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   18.5723  -16.3356    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   19.2594  -16.7318    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   19.9465  -16.3356    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
   19.2594  -17.5242    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
   17.8811  -17.5242    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
   20.6294  -16.7318    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   21.5104  -16.3603    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   20.6294  -17.5242    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   19.9465  -17.9204    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   21.3165  -17.9204    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   16.4902  -16.7395    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   22.0789  -16.9392    0.0000 O   0  0  0  0  0  0  0  0  0  0  0  0
   16.4881  -17.5567    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   15.8316  -18.0361    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   16.0822  -18.8139    0.0000 S   0  0  0  0  0  0  0  0  0  0  0  0
   16.8994  -18.8160    0.0000 C   0  0  0  0  0  0  0  0  0  0  0  0
   17.1538  -18.0394    0.0000 N   0  0  0  0  0  0  0  0  0  0  0  0
  1  2  1  0
  2  3  1  0
  3  4  1  0
  4  5  1  0
  5  6  1  0
  6  7  1  0
  7  8  1  0
  1  9  1  0
  8 10  1  0
 10 11  1  0
  9 12  1  0
 12 13  1  0
 13 14  2  0
 13 15  1  0
 15 16  1  0
 16 17  1  0
 17 18  1  0
 18 19  1  0
 19 20  1  0
 19 21  2  0
 17 22  1  6
 20 23  1  0
 23 24  1  0
 23 25  1  6
 25 26  1  0
 25 27  1  0
 24 11  1  0
 16 28  1  6
 24 29  2  0
 28 30  1  0
 30 31  2  0
 31 32  1  0
 32 33  1  0
 33 34  2  0
 34 30  1  0
M  END

Alternative Forms

1. Parent:

   

   ALA4451023

   ---

Molecule Features

Natural Product: No

Oral: No

Chemical Probe: No

Parenteral: No

Molecule Type: Unknown

Topical: No

First In Class: No

Black Box: No

Chirality: No

Availability: No

Prodrug: No

Calculated Properties

Molecular Weight: 494.70

Molecular Weight (Monoisotopic): 494.2927

AlogP: 3.09

#Rotatable Bonds: 3

Polar Surface Area: 120.42

Molecular Species: NEUTRAL

HBA: 6

HBD: 4

#RO5 Violations: ┄

HBA (Lipinski): 8

HBD (Lipinski): 4

#RO5 Violations (Lipinski): ┄

CX Acidic pKa: 12.47

CX Basic pKa: 2.46

CX LogP: 2.59

CX LogD: 2.59

Aromatic Rings: 1

Heavy Atoms: 34

QED Weighted: 0.51

Np Likeness Score: 0.32

References

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3. Ersmark, Karolina K and 9 more authors.  2004-01-01  Potent inhibitors of the Plasmodium falciparum enzymes plasmepsin I and II devoid of cathepsin D inhibitory activity.  [PMID:14695825]

4. Johansson, Per-Ola PO and 10 more authors.  2004-06-17  Design and synthesis of potent inhibitors of the malaria aspartyl proteases plasmepsin I and II. Use of solid-phase synthesis to explore novel statine motifs.  [PMID:15189032]

5. Johansson, Per-Ola PO and 8 more authors.  2005-06-30  Design and synthesis of potent inhibitors of plasmepsin I and II: X-ray crystal structure of inhibitor in complex with plasmepsin II.  [PMID:15974592]

6. Jennings, Lee D LD and 20 more authors.  2008-01-15  Acylguanidine inhibitors of beta-secretase: optimization of the pyrrole ring substituents extending into the S1' substrate binding pocket.  [PMID:18068983]

7. Clarke, Brian B and 26 more authors.  2008-02-01  BACE-1 inhibitors part 1: identification of novel hydroxy ethylamines (HEAs).  [PMID:18171614]

8. Charrier, Nicolas N and 24 more authors.  2008-06-12  Second generation of hydroxyethylamine BACE-1 inhibitors: optimizing potency and oral bioavailability.  [PMID:18457381]

9. and Ghosh, Arun K.  2009-04-23  Harnessing nature's insight: design of aspartyl protease inhibitors from treatment of drug-resistant HIV to Alzheimer's disease.  [PMID:19323561]

10. Charrier, Nicolas N and 23 more authors.  2009-07-01  Second generation of BACE-1 inhibitors. Part 1: The need for improved pharmacokinetics.  [PMID:19428244]

11. Charrier, Nicolas N and 21 more authors.  2009-07-01  Second generation of BACE-1 inhibitors part 2: Optimisation of the non-prime side substituent.  [PMID:19477642]

12. Orrling, Kristina M KM and 5 more authors.  2009-08-15  alpha-Substituted norstatines as the transition-state mimic in inhibitors of multiple digestive vacuole malaria aspartic proteases.  [PMID:19635672]

13. Kwan, Jason C; Eksioglu, Erika A; Liu, Chen; Paul, Valerie J and Luesch, Hendrik.  2009-09-24  Grassystatins A-C from marine cyanobacteria, potent cathepsin E inhibitors that reduce antigen presentation.  [PMID:19715320]

14. Malamas, Michael S MS and 13 more authors.  2010-02-11  Design and synthesis of 5,5'-disubstituted aminohydantoins as potent and selective human beta-secretase (BACE1) inhibitors.  [PMID:19968289]

15. Malamas, Michael S MS and 17 more authors.  2010-04-01  Novel pyrrolyl 2-aminopyridines as potent and selective human beta-secretase (BACE1) inhibitors.  [PMID:20223661]

16. Gupta, Deepak D, Yedidi, Ravikiran S RS, Varghese, Sheeba S, Kovari, Ladislau C LC and Woster, Patrick M PM.  2010-05-27  Mechanism-based inhibitors of the aspartyl protease plasmepsin II as potential antimalarial agents.  [PMID:20438064]

17. Clarke, Brian B and 21 more authors.  2010-08-01  BACE-1 hydroxyethylamine inhibitors using novel edge-to-face interaction with Arg-296.  [PMID:20579874]

18. Malamas, Michael S MS and 14 more authors.  2011-09-15  New pyrazolyl and thienyl aminohydantoins as potent BACE1 inhibitors: exploring the S2' region.  [PMID:21835615]

19. Monenschein, Holger H and 7 more authors.  2012-06-01  Structure guided P1' modifications of HEA derived β-secretase inhibitors for the treatment of Alzheimer's disease.  [PMID:22572583]

20. Ghosh, Arun K and 7 more authors.  2012-11-08  Structure-based design of highly selective β-secretase inhibitors: synthesis, biological evaluation, and protein-ligand X-ray crystal structure.  [PMID:22954357]

21. Liu, Yanxia Y and 13 more authors.  2012-12-13  Cyanobacterial peptides as a prototype for the design of potent β-secretase inhibitors and the development of selective chemical probes for other aspartic proteases.  [PMID:23181502]

22. Hunt, Kevin W KW and 25 more authors.  2013-04-25  Spirocyclic β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors: from hit to lowering of cerebrospinal fluid (CSF) amyloid β in a higher species.  [PMID:23537249]

23. Ghosh, Arun K and 10 more authors.  2015-02-01  Structure-based design, synthesis and biological evaluation of novel β-secretase inhibitors containing a pyrazole or thiazole moiety as the P3 ligand.  [PMID:25537272]

24. Chen, Jian Jeffrey JJ and 36 more authors.  2015-02-15  Development of 2-aminooxazoline 3-azaxanthenes as orally efficacious β-secretase inhibitors for the potential treatment of Alzheimer's disease.  [PMID:25613679]

25. Al-Awadhi, Fatma H; Ratnayake, Ranjala; Paul, Valerie J and Luesch, Hendrik.  2016-08-01  Tasiamide F, a potent inhibitor of cathepsins D and E from a marine cyanobacterium.  [PMID:27211244]

26. Al-Awadhi, Fatma H FH, Law, Brian K BK, Paul, Valerie J VJ and Luesch, Hendrik H.  2017-11-22  Grassystatins D-F, Potent Aspartic Protease Inhibitors from Marine Cyanobacteria as Potential Antimetastatic Agents Targeting Invasive Breast Cancer.  [PMID:29087712]

27. Low, Jonathan D JD and 14 more authors.  2017-06-01  Development of 2-aminooxazoline 3-azaxanthene β-amyloid cleaving enzyme (BACE) inhibitors with improved selectivity against Cathepsin D.  [PMID:30108829]

28. Zogota, Rimants R and 10 more authors.  2019-02-01  Peptidomimetic plasmepsin inhibitors with potent anti-malarial activity and selectivity against cathepsin D.  [PMID:30529637]

29. Pettus, Liping H and 14 more authors.  2020-03-12  Discovery of AM-6494: A Potent and Orally Efficacious β-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitor with in Vivo Selectivity over BACE2.  [PMID:31589043]

30. Goyal, Sandeep and 11 more authors.  2021-01-01  Identification and structure-activity relationship studies of small molecule inhibitors of the human cathepsin D.  [PMID:33271453]

Source

Source(1):

• Scientific Literature