Belumosudil

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

Structure Search

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)

HIDE SMILES / InChI

Description
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

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Rho-associated protein kinase 2 25 Target ID: CHEMBL2973 Sources: https://www.ncbi.nlm.nih.gov/pubmed/24466563	Inhibitor 8297	60.0 nM [IC50]
Interleukin 17A 8 Target ID: CHEMBL3390822 Sources: https://www.ncbi.nlm.nih.gov/pubmed/25385601	Inhibitor 8297
Interleukin-21 3 Target ID: Q9HBE4 Gene ID: 59067.0 Gene Symbol: IL21 Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/25385601	Inhibitor 8297

Conditions

Condition	Modality	Targets	Highest Phase	Product
Psoriasis 84 Sources: https://clinicaltrials.gov/ct2/show/NCT02852967	Primary		Phase II 1132	Unknown Approved Use Unknown
Idiopathic pulmonary fibrosis 10 Sources: https://clinicaltrials.gov/ct2/show/NCT02688647	Primary		Phase II 1132	Unknown Approved Use Unknown

C_max

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

T_1/2

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: https://pubmed.ncbi.nlm.nih.gov/28389592 Page: p.3811	unhealthy n = 7 Health Status: unhealthy Condition: psoriasis Sex: M+F Food Status: UNKNOWN Population Size: 7 Sources: https://pubmed.ncbi.nlm.nih.gov/28389592 Page: p.3811	Disc. AE: ALT increased, AST increased... AEs leading to discontinuation/dose reduction: ALT increased (33.3%) AST increased (33.3%) Sources: https://pubmed.ncbi.nlm.nih.gov/28389592 Page: p.3811

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: https://pubmed.ncbi.nlm.nih.gov/28389592 Page: p.3811	unhealthy n = 7 Health Status: unhealthy Condition: psoriasis Sex: M+F Food Status: UNKNOWN Population Size: 7 Sources: https://pubmed.ncbi.nlm.nih.gov/28389592 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: https://pubmed.ncbi.nlm.nih.gov/28389592 Page: p.3811	unhealthy n = 7 Health Status: unhealthy Condition: psoriasis Sex: M+F Food Status: UNKNOWN Population Size: 7 Sources: https://pubmed.ncbi.nlm.nih.gov/28389592 Page: p.3811

Sourcing

Vendor/Aggregator	ID	URL
1PlusChem LLC	1P003AXB	https://www.1pchem.com/search?query=1P003AXB
AChemBlock	L13971	http://www.achemblock.com/catalogsearch/result/?q=L13971
AK Scientific	4050AH	https://aksci.com/item_detail.php?cat=4050AH
Ambeed	A255643	http://www.ambeed.com/search/Search.html?keyword=A255643
ApexBio Technology	A3825	https://www.apexbt.com/catalogsearch/result/?q=A3825
AstaTech	42507	http://astatechinc.com/CPSResult.php?CRNO=42507
Axon MedChem	2780	https://www.axonmedchem.com/product/2780
BLD Pharm	BD448309	http://www.bldpharm.com/search/Search.html?keyword=BD448309
Cayman Chemical	17055	http://www.caymanchem.com/app/template/Product.vm/catalog/17055
Chem Scene	CS-0776	http://www.chemscene.com/goproductList/searchProductList?productObj=CS-0776
ChemShuttle	152129	https://www.chemshuttle.com/catalogsearch/result/?q=152129
Combi-Blocks	QV-8526	http://www.combi-blocks.com/cgi-bin/find.cgi?QV-8526
Excenen	EX-A2314	http://www.excenen.com/searchresultlist.php?id=EX-A2314
KeyOrganics	AS-35230	http://www.keyorganicsinc.com/bionet/catalogsearch/result?q=AS-35230
MedChem Express	HY-15307	https://www.medchemexpress.com/search.html?q=HY-15307&ft=&fa=&fp=
MolPort	MolPort-039-139-806	https://www.molport.com/shop/molecule-link/MolPort-039-139-806
MuseChem	I005432	https://www.musechem.com/product/I005432.html
Selleck Chemicals	S7936	http://www.selleckchem.com/search.html?searchDTO.searchParam=S7936
ShangHai Biochempartner	BCP15921	http://www.biochempartner.com/search_BCP15921
eMolecules	44811418	https://orderbb.emolecules.com/search/#?query=44811418
mcule	MCULE-6423720146	https://mcule.com/MCULE-6423720146/

PubMed

Title	Date	PubMed
Selective oral ROCK2 inhibitor down-regulates IL-21 and IL-17 secretion in human T cells via STAT3-dependent mechanism.	2014 Nov 25	25385601
Targeted Rho-associated kinase 2 inhibition suppresses murine and human chronic GVHD through a Stat3-dependent mechanism.	2016 Apr 28	26983850
ROCK2 signaling is required to induce a subset of T follicular helper cells through opposing effects on STATs in autoimmune settings.	2016 Jul 19	27436361

Patents

Sample Use Guides

In Vivo Use Guide

KD025 dose of 200 mg daily for 4 weeks

Route of Administration: Oral

In Vitro Use Guide

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

Name

Type

Language

Belumosudil

Official Name

English

ROCK2 INHIBITOR KD025

Common Name

English

belumosudil [INN]

Common Name

English

KD-025

Code

English

ACETAMIDE, 2-(3-(4-(1H-INDAZOL-5-YLAMINO)-2-QUINAZOLINYL)PHENOXY)-N-(1-METHYLETHYL)-

Systematic Name

English

BELUMOSUDIL [USAN]

Common Name

English

2-(3-(4-((1H-INDAZOL-5-YL)AMINO)QUINAZOLIN-2-YL)PHENOXY)-N-ISOPROPYLACETAMIDE

Systematic Name

English

SLX-2119 FREE BASE

Common Name

English

Belumosudil [WHO-DD]

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C61074