Details
Stereochemistry | ACHIRAL |
Molecular Formula | C26H24N6O2 |
Molecular Weight | 452.5078 |
Optical Activity | NONE |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
CC(C)NC(=O)COC1=CC=CC(=C1)C2=NC3=C(C=CC=C3)C(NC4=CC=C5NN=CC5=C4)=N2
InChI
InChIKey=GKHIVNAUVKXIIY-UHFFFAOYSA-N
InChI=1S/C26H24N6O2/c1-16(2)28-24(33)15-34-20-7-5-6-17(13-20)25-30-23-9-4-3-8-21(23)26(31-25)29-19-10-11-22-18(12-19)14-27-32-22/h3-14,16H,15H2,1-2H3,(H,27,32)(H,28,33)(H,29,30,31)
Molecular Formula | C26H24N6O2 |
Molecular Weight | 452.5078 |
Charge | 0 |
Count |
|
Stereochemistry | ACHIRAL |
Additional Stereochemistry | No |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Optical Activity | NONE |
DescriptionSources: http://www.jefferies.com/CMSFiles/Jefferies.com/files/Conferences/060214/Presentations/Kadmon%20Corp.pdfCurator's Comment: Description was created based on several sources, including
http://kadmon.com/research-development/pipeline/
http://en.pharmacodia.com/web/drug/1_1994.html
Sources: http://www.jefferies.com/CMSFiles/Jefferies.com/files/Conferences/060214/Presentations/Kadmon%20Corp.pdf
Curator's Comment: Description was created based on several sources, including
http://kadmon.com/research-development/pipeline/
http://en.pharmacodia.com/web/drug/1_1994.html
KD025 is an orally available, selective small molecule inhibitor of ROCK2 (Rho-associated coiled-coil kinase 2), a molecular target in multiple autoimmune, fibrotic and neurodegenerative diseases. KD025 is the only ROCK2-specific inhibitor in the clinical trials. KD025 down-regulates the IL-17 and IL-21 secretion in human PBMCs, and leads to down-regulation of STAT3 phosphorylation, IRF4, and RORγt expression in CD4+ T cells. Kadmon Pharmaceuticals initiated phase II clinical trials of KD025 for the treatment of Graft-versus-host disease; Idiopathic pulmonary fibrosis; Plaque psoriasis.
CNS Activity
Sources: http://www.jefferies.com/CMSFiles/Jefferies.com/files/Conferences/060214/Presentations/Kadmon%20Corp.pdf
Curator's Comment: Excellent brain penetration
Originator
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: CHEMBL2973 Sources: https://www.ncbi.nlm.nih.gov/pubmed/24466563 |
60.0 nM [IC50] | ||
Target ID: CHEMBL3390822 Sources: https://www.ncbi.nlm.nih.gov/pubmed/25385601 |
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Target ID: Q9HBE4 Gene ID: 59067.0 Gene Symbol: IL21 Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/25385601 |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
---|---|---|---|---|
Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
Cmax
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
128.4 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/32192179 |
5 mg/kg single, oral dose: 5 mg/kg route of administration: Oral experiment type: SINGLE co-administered: |
KD-025 FREE BASE plasma | Rattus norvegicus population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FED |
AUC
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
48.7 μg × min/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/32192179 |
5 mg/kg single, oral dose: 5 mg/kg route of administration: Oral experiment type: SINGLE co-administered: |
KD-025 FREE BASE plasma | Rattus norvegicus population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FED |
T1/2
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
353.4 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/32192179 |
5 mg/kg single, oral dose: 5 mg/kg route of administration: Oral experiment type: SINGLE co-administered: |
KD-025 FREE BASE plasma | Rattus norvegicus population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FED |
Doses
Dose | Population | Adverse events |
---|---|---|
400 mg 2 times / day multiple, oral Highest studied dose Dose: 400 mg, 2 times / day Route: oral Route: multiple Dose: 400 mg, 2 times / day Sources: Page: p.3811 |
unhealthy n = 7 Health Status: unhealthy Condition: psoriasis Sex: M+F Food Status: UNKNOWN Population Size: 7 Sources: Page: p.3811 |
Disc. AE: ALT increased, AST increased... AEs leading to discontinuation/dose reduction: ALT increased (33.3%) Sources: Page: p.3811AST increased (33.3%) |
AEs
AE | Significance | Dose | Population |
---|---|---|---|
ALT increased | 33.3% Disc. AE |
400 mg 2 times / day multiple, oral Highest studied dose Dose: 400 mg, 2 times / day Route: oral Route: multiple Dose: 400 mg, 2 times / day Sources: Page: p.3811 |
unhealthy n = 7 Health Status: unhealthy Condition: psoriasis Sex: M+F Food Status: UNKNOWN Population Size: 7 Sources: Page: p.3811 |
AST increased | 33.3% Disc. AE |
400 mg 2 times / day multiple, oral Highest studied dose Dose: 400 mg, 2 times / day Route: oral Route: multiple Dose: 400 mg, 2 times / day Sources: Page: p.3811 |
unhealthy n = 7 Health Status: unhealthy Condition: psoriasis Sex: M+F Food Status: UNKNOWN Population Size: 7 Sources: Page: p.3811 |
Sample Use Guides
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/24466563
KD025 selectively inhibited ROCK2 with IC50 values ~60 nmol/L, but had little effect on ROCK1 enzymatic activity at concentrations up to 10 umol/L in a recombinant enzyme system
Substance Class |
Chemical
Created
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Record UNII |
834YJF89WO
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Validated (UNII)
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NCI_THESAURUS |
C61074
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FDA ORPHAN DRUG |
760520
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2564025
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11343
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834YJF89WO
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Belumosudil
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11950170
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DTXSID80238425
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C128786
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911417-87-3
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100000183980
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FG-181
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834YJF89WO
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Related Record | Type | Details | ||
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METABOLIC ENZYME -> INHIBITOR |
Inhibits at clinically relevant concentrations.
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SALT/SOLVATE -> PARENT |
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METABOLIC ENZYME -> INHIBITOR |
Inhibits at clinically relevant concentrations.
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BINDER->LIGAND |
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EXCRETED UNCHANGED |
FECAL
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CUMULATIVE EXCRETION |
URINE
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METABOLIC ENZYME -> SUBSTRATE |
Based on in vitro assessment, CYP3A4 (41.9%) was the predominant cytochrome P450 (CYP) isoform responsible for the metabolism of belumosudil.
MAJOR
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SALT/SOLVATE -> PARENT |
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TRANSPORTER -> INHIBITOR |
Inhibits at clinically relevant concentrations.
|
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|
METABOLIC ENZYME -> SUBSTRATE |
Based on in vitro assessment, CYP3A4 (41.9%) was the predominant cytochrome P450 (CYP) isoform responsible for the metabolism of belumosudil
although CYP2D6 (21.7%), CYP2C8 (14.2%), CYP1A2 (<5%), CYP2C19 (<5%), and UGT1A9 may
also contribute to a lesser extent
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TRANSPORTER -> SUBSTRATE |
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TRANSPORTER -> INHIBITOR |
Inhibits at clinically relevant concentrations.
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METABOLIC ENZYME -> INHIBITOR |
Inhibits at clinically relevant concentrations.
|
||
|
METABOLIC ENZYME -> SUBSTRATE |
Based on in vitro assessment, CYP3A4 (41.9%) was the
predominant cytochrome P450 (CYP) isoform responsible for the metabolism of belumosudil
although CYP2D6 (21.7%), CYP2C8 (14.2%), CYP1A2 (<5%), CYP2C19 (<5%), and UGT1A9 may
also contribute to a lesser extent
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EXCRETED UNCHANGED |
FECAL
|
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CUMULATIVE EXCRETION |
FECAL
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METABOLIC ENZYME -> INHIBITOR |
Inhibits at clinically relevant concentrations.
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TARGET -> INHIBITOR |
Inhibits signal transducer and activator of transcription 3 (STAT3) phosphorylation. Shifts T helper 17 (Th17)/T regulatory (Treg) balance towards the Treg phenotype
IC50
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TRANSPORTER -> INHIBITOR |
Inhibits at clinically relevant concentrations.
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METABOLIC ENZYME -> INHIBITOR |
Inhibits at clinically relevant concentrations.
|
Related Record | Type | Details | ||
---|---|---|---|---|
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METABOLITE LESS ACTIVE -> PARENT |
MAJOR
FECAL; PLASMA; URINE
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METABOLITE ACTIVE -> PARENT |
MINOR
PLASMA
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Related Record | Type | Details | ||
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ACTIVE MOIETY |
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Name | Property Type | Amount | Referenced Substance | Defining | Parameters | References |
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Biological Half-life | PHARMACOKINETIC |
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Volume of Distribution | PHARMACOKINETIC |
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