ACT-1014-6470   Click here for help

GtoPdb Ligand ID: 12326

Synonyms: example 172 [WO2019137927A1] [2] | Ic-58 [2]
Immunopharmacology Ligand
Compound class: Synthetic organic
Comment: ACT-1014-6470 is a novel, orally available small molecule anatgonist of the complement factor 5a receptor 1 (C5a1 receptor) [4]. It was designed for anti-inflammatory activity, for application in autoimmune diseases. ACT-1014-6470 selectively targets C5a-mediated receptor signalling, in contrast to the clinically used anti-C5 monoclonals eculizumab and ravulizumab that prevent C5a (anaphylatoxin) and C5b production. The principal effect of both strategies is to block further activation of complement-mediated inflammation. One suggested benefit of the small-molecule approach is that it does not alter C5b-mediated membrane attack complex (MAC) formation, which means that the bactericidal activity of the complement system remains intact.

n.b. Avacopan (CCX-168) was the first C5a1 receptor antagonist to be approved by the FDA (2021).
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Ligand Activity Visualisation Charts

These are box plot that provide a unique visualisation, summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Click on a plot to see the median, interquartile range, low and high data points. A value of zero indicates that no data are available. A separate chart is created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts.

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View interactive charts of activity data across species
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 5
Hydrogen bond donors 0
Rotatable bonds 7
Topological polar surface area 44.61
Molecular weight 565.23
XLogP 7.03
No. Lipinski's rules broken 1

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 O=C1N(Cc2c(N1Cc1ccccc1C(F)(F)F)nn(c2)CC(F)(F)C)C1CCN(CC1)c1c(C)cccc1F
Isomeric SMILES FC(Cn1nc2N(C(=O)N(Cc2c1)C1CCN(CC1)c1c(cccc1C)F)Cc1c(cccc1)C(F)(F)F)(C)F
InChI InChI=1S/C28H29F6N5O/c1-18-6-5-9-23(29)24(18)36-12-10-21(11-13-36)38-16-20-14-37(17-27(2,30)31)35-25(20)39(26(38)40)15-19-7-3-4-8-22(19)28(32,33)34/h3-9,14,21H,10-13,15-17H2,1-2H3
InChI Key YPWBQOVYMUEXJT-UHFFFAOYSA-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. Anliker-Ort M, Dingemanse J, Farine H, Groenen P, Kornberger R, van den Anker J, Kaufmann P. (2023)
Multiple-ascending doses of ACT-1014-6470, an oral complement factor 5a receptor 1 (C5a1 receptor) antagonist: Tolerability, pharmacokinetics and target engagement.
Br J Clin Pharmacol, 89 (1): 380-389. [PMID:36000981]
2. Froidevaux S, Hubler F, Murphy M, Rennenberg D, Stamm S. (2019)
2,4,6,7-tetrahydro-pyrazolo[4,3-d]pyrimidin-5-one derivatives and related compounds as c5a receptor modulators for treating vasculitis and inflammatory diseases.
Patent number: WO2019137927A1. Assignee: Idorsia Pharmaceuticals Ltd. Priority date: 09/01/2019. Publication date: 18/07/2019.
3. Hammann-Hänni A, Kaufmann P, Klein G, Schmid K, Dingemanse J. (2023)
Effect of Severe Renal Impairment on Pharmacokinetics, Safety, and Tolerability of ACT-1014-6470, a Novel Oral Complement Factor 5a Receptor 1 Antagonist.
Clin Pharmacol Drug Dev, 12 (2): 152-158. [PMID:36285509]
4. Ort M, Dingemanse J, Hsin CH, Richard M, Huehn E, Sabattini G, van de Wetering J, Kornberger R, van den Anker J, Kaufmann P. (2022)
First-in-human study with ACT-1014-6470, a novel oral complement factor 5a receptor 1 (C5aR1) antagonist, supported by pharmacokinetic predictions from animals to patients.
Basic Clin Pharmacol Toxicol, 131 (2): 114-128. [PMID:35596117]