fosigotifator   Click here for help

GtoPdb Ligand ID: 12886

Synonyms: ABBV-CLS-7262 | compound 131 [US20220251123A1]
Compound class: Synthetic organic
Comment: The structure for fosigotifator was obtained from proposed INN list 129 (August 2023) where it is described as a eukaryotic translation initiation factor 2B (eIF2B) activator. Fosigotifator is one of the prodrug compounds claimed in patent US20220251123A1 [2]. It is likely that this is the Abbvie/Calico oral, CNS-penetrant clinical lead ABBV-CLS-7262, that is designed to activate eIF2B and thereby modulate the integrated stress response (ISR) [4] as a mechanism to treat a range of conditions, including neurodegenerative and metabolic diseases [1,3,5].
2D Structure
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2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

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Physico-chemical Properties
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Physico-chemical Properties

Calculated molecular properties are available for small molecules and natural products (not peptides). Properties were generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/). All properties were selected to enable the prediction of the Lipinski Rule-of-Five profile or ‘druglikeness’ for each ligand. For more info on each category see the help pages.

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Hydrogen bond acceptors 11
Hydrogen bond donors 4
Rotatable bonds 14
Topological polar surface area 162.46
Molecular weight 639.37
XLogP 1.11
No. Lipinski's rules broken 3

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)
SMILES / InChI / InChIKey
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SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)

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Canonical SMILES C1=C(C=C(C(=C1)Cl)F)OCC(=O)NC23CCC(CC2)([C@H](C3)OCOP(=O)(O)O)NC(=O)COC4=CC=C(C(=C4)F)Cl
Isomeric SMILES C1CC2(CCC1(C[C@@H]2OCOP(=O)(O)O)NC(=O)COC3=CC(=C(C=C3)Cl)F)NC(=O)COC4=CC(=C(C=C4)Cl)F
InChI InChI=1S/C25H27Cl2F2N2O9P/c26-17-3-1-15(9-19(17)28)37-12-22(32)30-24-5-7-25(8-6-24,21(11-24)39-14-40-41(34,35)36)31-23(33)13-38-16-2-4-18(27)20(29)10-16/h1-4,9-10,21H,5-8,11-14H2,(H,30,32)(H,31,33)(H2,34,35,36)/t21-,24?,25?/m0/s1
InChI Key IURMHIZNAHLQRX-ANYOXOOPSA-N

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)
References
1. Hanson FM, Hodgson RE, de Oliveira MIR, Allen KE, Campbell SG. (2022)
Regulation and function of elF2B in neurological and metabolic disorders.
Biosci Rep, 42 (6). [PMID:35579296]
2. Martin KA, Sidrauski C, Dart MJ, Frost JM, Tong Y, Xu X, Shi L, Murauski K, Pliuschev M, Brown BS et al.. (2022)
Prodrug modulators of the integrated stress pathway.
Patent number: US20220251123A1. Assignee: AbbVie Inc Calico Life Sciences LLC. Priority date: 02/09/2021. Publication date: 11/08/2022.
3. Norris K, Hodgson RE, Dornelles T, Allen KE, Abell BM, Ashe MP, Campbell SG. (2021)
Mutational analysis of the alpha subunit of eIF2B provides insights into the role of eIF2B bodies in translational control and VWM disease.
J Biol Chem, 296: 100207. [PMID:33334879]
4. Schoof M, Boone M, Wang L, Lawrence R, Frost A, Walter P. (2021)
eIF2B conformation and assembly state regulate the integrated stress response.
Elife, 10. [PMID:33688831]
5. Slynko I, Nguyen S, Hamilton EMC, Wisse LE, de Esch IJP, de Graaf C, Bruning JB, Proud CG, Abbink TEM, van der Knaap MS. (2021)
Vanishing white matter: Eukaryotic initiation factor 2B model and the impact of missense mutations.
Mol Genet Genomic Med, 9 (3): e1593. [PMID:33432707]