(4aS,8aR)-4-(3-(4-(4-(1H-tetrazol-5-yl)phenoxy)butoxy)-4-methoxyphenyl)-2-cycloheptyl-4a,5,8,8a-tetrahydrophthalazin-1(2H)-one

ID: ALA2326941

Chembl Id: CHEMBL2326941

Cas Number: 2366272-43-5

PubChem CID: 71719394

Max Phase: Preclinical

Molecular Formula: C33H40N6O4

Molecular Weight: 584.72

Molecule Type: Small molecule

Names and Identifiers

Canonical SMILES:  COc1ccc(C2=NN(C3CCCCCC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OCCCCOc1ccc(-c2nnn[nH]2)cc1

Standard InChI:  InChI=1S/C33H40N6O4/c1-41-29-19-16-24(31-27-12-6-7-13-28(27)33(40)39(36-31)25-10-4-2-3-5-11-25)22-30(29)43-21-9-8-20-42-26-17-14-23(15-18-26)32-34-37-38-35-32/h6-7,14-19,22,25,27-28H,2-5,8-13,20-21H2,1H3,(H,34,35,37,38)/t27-,28+/m0/s1

Standard InChI Key:  DNDNLFXKQSTINI-WUFINQPMSA-N

Alternative Forms

1. Parent:

   

   ALA2326941

   Dnmt3A-IN-2

Molecule Features

Natural Product: Yes

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: 584.72

Molecular Weight (Monoisotopic): 584.3111

AlogP: 5.96

#Rotatable Bonds: 11

Polar Surface Area: 114.82

Molecular Species: ACID

HBA: 8

HBD: 1

#RO5 Violations: 2

HBA (Lipinski): 10

HBD (Lipinski): 1

#RO5 Violations (Lipinski): 2

CX Acidic pKa: 4.33

CX Basic pKa: 1.38

CX LogP: 5.81

CX LogD: 4.21

Aromatic Rings: 3

Heavy Atoms: 43

QED Weighted: 0.17

Np Likeness Score: -0.75

References

1. Jansen C, Wang H, Kooistra AJ, de Graaf C, Orrling KM, Tenor H, Seebeck T, Bailey D, de Esch IJ, Ke H, Leurs R..  (2013)  Discovery of novel Trypanosoma brucei phosphodiesterase B1 inhibitors by virtual screening against the unliganded TbrPDEB1 crystal structure.,  56  (5): [PMID:23409953] [10.1021/jm3017877]

2. MMV Pathogen Box,  [10.6019/CHEMBL3637841]

3. Veerman J, van den Bergh T, Orrling KM, Jansen C, Cos P, Maes L, Chatelain E, Ioset JR, Edink EE, Tenor H, Seebeck T, de Esch I, Leurs R, Sterk GJ..  (2016)  Synthesis and evaluation of analogs of the phenylpyridazinone NPD-001 as potent trypanosomal TbrPDEB1 phosphodiesterase inhibitors and in vitro trypanocidals.,  24  (7): [PMID:26935942] [10.1016/j.bmc.2016.02.032]

4. Nathan group, Weill Cornell Medical College; Barry Lab, NIAID NIH; Winzeler lab, UCSD; Laboratory of Microbiology, Parasitology and Hygiene (LMPH), Univ. of Antwerp; London School of Hygiene and Tropical Medicine; Parasite Chemotherapy Unit at Swiss Tropical and Public Health Institute; Huston group at the University of Vermont; Castellanos group at UTMB, Galveston, Texas; Sakanari Lab, Univ. of Calif. San Francisco; Townson (Simon) Lab, Imperial College London; Fidelis Cho-Ngwa Lab, University of Buea, Buea, Cameroon; Laboratory of Molecular Parasitology at the New York Blood Center; Bickle Lab, London School of Hygiene and Tropical Medicine; Keiser Lab, Swiss Tropical and Public Health Institute; Caffrey group at the Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, UC San Diego; University of Cape Town; Shanmugam group at CSIR-National Chemical Laboratory, Pune (India); Novartis Institute for Tropical Disease-Singapore; Abbvie. MMV Pathogen Box Bioactivity Data,  [10.6019/CHEMBL3832761]

5. Anna Ehmann. The Australian National University Dept Of Immunology Pathogen Box Compounds Screened,  [10.6019/CHEMBL3987221]

6. Blaazer AR, Singh AK, de Heuvel E, Edink E, Orrling KM, Veerman JJN, van den Bergh T, Jansen C, Balasubramaniam E, Mooij WJ, Custers H, Sijm M, Tagoe DNA, Kalejaiye TD, Munday JC, Tenor H, Matheeussen A, Wijtmans M, Siderius M, de Graaf C, Maes L, de Koning HP, Bailey DS, Sterk GJ, de Esch IJP, Brown DG, Leurs R..  (2018)  Targeting a Subpocket in Trypanosoma brucei Phosphodiesterase B1 (TbrPDEB1) Enables the Structure-Based Discovery of Selective Inhibitors with Trypanocidal Activity.,  61  (9): [PMID:29672041] [10.1021/acs.jmedchem.7b01670]

7. Veale CGL, Hoppe HC..  (2018)  Screening of the Pathogen Box reveals new starting points for anti-trypanosomal drug discovery.,  9  (12): [PMID:30647879] [10.1039/C8MD00319J]

8. Sarink, M; Mykytyn, A; Tielens, A; van Hellemond, J. Naegleria gruberi Pathogen Box compounds screening,  [10.6019/CHEMBL4513101]

9. Johannes Zuegg, Alysha Elliott, Maite Amado, Emma Cowie, Ali Hinton, Geraldine Kaeslin, Angela Kavanagh, Anne Kunert, Gabriell Lowe, Soumya Ramu, Janet Reid, Robin Trauer, Mathilde Desselle, Ruth Neale, Karl Hansford, Mark Blascovich, Matthew Cooper. CO-ADD screening of MMV (CH) - MMV compounds,  [10.6019/CHEMBL4513149]

10. Huang S, Stillson NJ, Sandoval JE, Yung C, Reich NO..  (2021)  A novel class of selective non-nucleoside inhibitors of human DNA methyltransferase 3A.,  40  [PMID:33705897] [10.1016/j.bmcl.2021.127908]

11. Sandoval JE, Ramabadran R, Stillson N, Sarah L, Fujimori DG, Goodell MA, Reich N..  (2022)  First-in-Class Allosteric Inhibitors of DNMT3A Disrupt Protein-Protein Interactions and Induce Acute Myeloid Leukemia Cell Differentiation.,  65  (15.0): [PMID:35866897] [10.1021/acs.jmedchem.2c00725]

Source

Source(3):

• Scientific Literature
• MMV Pathogen Box
• CO-ADD antimicrobial screening data