lorecivivint   Click here for help

GtoPdb Ligand ID: 9620

Synonyms: adavivint (deprecated INN) | SM0-4690 | SM04690
Immunopharmacology Ligand
Compound class: Synthetic organic
Comment: Lorecivivint (SM04690, formerly adavivint) is a Wnt pathway inhibitor being developed by Samumed for immunomodulatory potential. It acts downstream of β-catenin, and its molecular targets are the intranuclear kinases CLK2 and DYRK1A through which it inhibits phosphorylation of serine/arginine-rich splicing factors, and SIRT1 and FOXO1 respectively [3]. Wnt signalling is upregulated in tissues from osteoarthritic joints, and drives disease pathologies including inflammation [5]. Wnt pathway inhibition by lorecivivint is being investigated as a disease-modifying treatment for osteoarthritis.
SM04690 is example 10 as claimed in patent US20160297812 [4]. The chemical structure shown here was produced using the IUPAC name submitted to the WHO for the INN adavivint (via SMILES generated using Chemicalize) which was later renamed as lorecivivint. This SMILES string resolves to PubChem CID 123710737, although some of the double bonds in the molecule are not fully resolved, when compared to the images in US20160297812. CID 89837869 is an alternative representation.
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Ligand Activity Visualisation Charts

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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 CDK toolkit. 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 6
Hydrogen bond donors 3
Rotatable bonds 7
Topological polar surface area 112.24
Molecular weight 505.2
XLogP 5.43
No. Lipinski's rules broken 1
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.

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Canonical SMILES CC(CC(=O)Nc1cncc(c1)c1ccc2c(c1)c(n[nH]2)c1nc2c([nH]1)c(cnc2)c1cccc(c1)F)C
Isomeric SMILES CC(CC(=O)Nc1cncc(c1)c1ccc2c(c1)c(n[nH]2)c1nc2c([nH]1)c(cnc2)c1cccc(c1)F)C
InChI InChI=1S/C29H24FN7O/c1-16(2)8-26(38)33-21-10-19(12-31-13-21)17-6-7-24-22(11-17)28(37-36-24)29-34-25-15-32-14-23(27(25)35-29)18-4-3-5-20(30)9-18/h3-7,9-16H,8H2,1-2H3,(H,33,38)(H,34,35)(H,36,37)
InChI Key AQDWDWAYVBQMAM-UHFFFAOYSA-N
References
1. Blom AB, Brockbank SM, van Lent PL, van Beuningen HM, Geurts J, Takahashi N, van der Kraan PM, van de Loo FA, Schreurs BW, Clements K et al.. (2009)
Involvement of the Wnt signaling pathway in experimental and human osteoarthritis: prominent role of Wnt-induced signaling protein 1.
Arthritis Rheum, 60 (2): 501-12. [PMID:19180479]
2. Deshmukh V, Hu H, Barroga C, Bossard C, Kc S, Dellamary L, Stewart J, Chiu K, Ibanez M, Pedraza M et al.. (2018)
A small-molecule inhibitor of the Wnt pathway (SM04690) as a potential disease modifying agent for the treatment of osteoarthritis of the knee.
Osteoarthr Cartil, 26 (1): 18-27. [PMID:28888902]
3. Deshmukh V, O'Green AL, Bossard C, Seo T, Lamangan L, Ibanez M, Ghias A, Lai C, Do L, Cho S et al.. (2019)
Modulation of the Wnt pathway through inhibition of CLK2 and DYRK1A by lorecivivint as a novel, potentially disease-modifying approach for knee osteoarthritis treatment.
Osteoarthr Cartil, 27 (9): 1347-1360. [PMID:31132406]
4. Hood J, Wallace DM, Kumar S. (2016)
INDAZOLE INHIBITORS OF THE WNT SIGNAL PATHWAY AND THERAPEUTIC USES THEREOF.
Patent number: US20160297812. Assignee: Samumed LLC. Priority date: 04/04/2012. Publication date: 13/10/2016.
5. Luyten FP, Tylzanowski P, Lories RJ. (2009)
Wnt signaling and osteoarthritis.
Bone, 44: 522-527. DOI: 10.1016/j.bone.2008.12.006
6. Maeda A, Ono M, Holmbeck K, Li L, Kilts TM, Kram V, Noonan ML, Yoshioka Y, McNerny EM, Tantillo MA et al.. (2015)
WNT1-induced Secreted Protein-1 (WISP1), a Novel Regulator of Bone Turnover and Wnt Signaling.
J Biol Chem, 290 (22): 14004-18. [PMID:25864198]
7. Yates KE, Shortkroff S, Reish RG. (2005)
Wnt influence on chondrocyte differentiation and cartilage function.
DNA Cell Biol, 24 (7): 446-57. [PMID:16008513]
8. Yazici Y, McAlindon TE, Fleischmann R, Gibofsky A, Lane NE, Kivitz AJ, Skrepnik N, Armas E, Swearingen CJ, DiFrancesco A et al.. (2017)
A novel Wnt pathway inhibitor, SM04690, for the treatment of moderate to severe osteoarthritis of the knee: results of a 24-week, randomized, controlled, phase 1 study.
Osteoarthr Cartil, 25 (10): 1598-1606. [PMID:28711582]