Drug Interactions: This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Not Available
Food Interactions: Not Available

Chemical Identifiers

UNII: HO1A8B3YVV
CAS number: 285983-48-4
InChI Key: MVCOAUNKQVWQHZ-UHFFFAOYSA-N
InChI: InChI=1S/C31H37N5O3/c1-22-9-11-23(12-10-22)36-29(21-28(34-36)31(2,3)4)33-30(37)32-26-13-14-27(25-8-6-5-7-24(25)26)39-20-17-35-15-18-38-19-16-35/h5-14,21H,15-20H2,1-4H3,(H2,32,33,37)
IUPAC Name: 3-[3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-1-{4-[2-(morpholin-4-yl)ethoxy]naphthalen-1-yl}urea
SMILES: CC1=CC=C(C=C1)N1N=C(C=C1NC(=O)NC1=CC=C(OCCN2CCOCC2)C2=C1C=CC=C2)C(C)(C)C

References

General References

Not Available

External Links

KEGG Drug: D03736
PubChem Compound: 156422
PubChem Substance: 46506062
ChemSpider: 137746
BindingDB: 13533
ChEBI: 40953
ChEMBL: CHEMBL103667
ZINC: ZINC000024044436
PDBe Ligand: B96

PDB Entries

1kv2 / 3fzs / 3npc / 4jvg / 4twn / 5n66 / 6gtt / 8ygw

Clinical Trials

Clinical Trials Clinical Trial & Rare Diseases Add-on Data Package Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package

Phase	Status	Purpose	Conditions	Count	Start Date	Why Stopped	100+ additional columns
Unlock 175K+ rows when you subscribe.View sample data
2	Completed	Treatment	Psoriasis	1	somestatus	stop reason	just information to hide
2	Terminated	Treatment	Rheumatoid Arthritis	1	somestatus	stop reason	just information to hide
1	Completed	Treatment	Healthy Volunteers (HV)	2	somestatus	stop reason	just information to hide

Pharmacoeconomics

Manufacturers: Not Available
Packagers: Not Available
Dosage Forms: Not Available
Prices: Not Available
Patents: Not Available

Properties

State

Solid

Experimental Properties

Not Available

Predicted Properties

Property	Value	Source
Water Solubility	0.00375 mg/mL	ALOGPS
logP	5.32	ALOGPS
logP	6.37	Chemaxon
logS	-5.2	ALOGPS
pKa (Strongest Acidic)	11.32	Chemaxon
pKa (Strongest Basic)	6.78	Chemaxon
Physiological Charge	0	Chemaxon
Hydrogen Acceptor Count	5	Chemaxon
Hydrogen Donor Count	2	Chemaxon
Polar Surface Area	80.65 Å²	Chemaxon
Rotatable Bond Count	8	Chemaxon
Refractivity	157.01 m³·mol^-1	Chemaxon
Polarizability	59.69 Å³	Chemaxon
Number of Rings	5	Chemaxon
Bioavailability	0	Chemaxon
Rule of Five	No	Chemaxon
Ghose Filter	No	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	Yes	Chemaxon

Predicted ADMET Features

Property	Value	Probability
Human Intestinal Absorption	+	1.0
Blood Brain Barrier	+	0.8737
Caco-2 permeable	-	0.532
P-glycoprotein substrate	Substrate	0.8156
P-glycoprotein inhibitor I	Inhibitor	0.8206
P-glycoprotein inhibitor II	Inhibitor	0.8018
Renal organic cation transporter	Non-inhibitor	0.6952
CYP450 2C9 substrate	Non-substrate	0.7781
CYP450 2D6 substrate	Non-substrate	0.7492
CYP450 3A4 substrate	Substrate	0.7602
CYP450 1A2 substrate	Non-inhibitor	0.8708
CYP450 2C9 inhibitor	Inhibitor	0.5409
CYP450 2D6 inhibitor	Non-inhibitor	0.8707
CYP450 2C19 inhibitor	Non-inhibitor	0.7406
CYP450 3A4 inhibitor	Inhibitor	0.5858
CYP450 inhibitory promiscuity	High CYP Inhibitory Promiscuity	0.6253
Ames test	Non AMES toxic	0.5569
Carcinogenicity	Non-carcinogens	0.7383
Biodegradation	Not ready biodegradable	1.0
Rat acute toxicity	2.6340 LD50, mol/kg	Not applicable
hERG inhibition (predictor I)	Strong inhibitor	0.51
hERG inhibition (predictor II)	Inhibitor	0.7139

ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	splash10-004i-0000090000-ed9deac1bb8fde147748
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	splash10-004i-1170090000-496346e5656055020e2d
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	splash10-004i-0450490000-d535801fb5b9aeceeeb7
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	splash10-004i-0792730000-3f651be32d778c343bdd
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	splash10-0ul0-9251430000-219c9339def9088368e2
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	splash10-01pk-0379300000-6b6eb3199d0b39da5757

Chromatographic Properties

Collision Cross Sections (CCS)

Adduct	CCS Value (Å²)	Source type	Source
[M-H]-	249.3472451	predicted	DarkChem Lite v0.1.0
[M-H]-	217.16966	predicted	DeepCCS 1.0 (2019)
[M+H]+	251.4470451	predicted	DarkChem Lite v0.1.0
[M+H]+	219.56523	predicted	DeepCCS 1.0 (2019)
[M+Na]+	250.2111451	predicted	DarkChem Lite v0.1.0
[M+Na]+	225.47777	predicted	DeepCCS 1.0 (2019)

Targets

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Details1. Tyrosine-protein kinase HCK

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Inhibitor

General Function: Non-receptor tyrosine-protein kinase found in hematopoietic cells that transmits signals from cell surface receptors and plays an important role in the regulation of innate immune responses, including neutrophil, monocyte, macrophage and mast cell functions, phagocytosis, cell survival and proliferation, cell adhesion and migration. Acts downstream of receptors that bind the Fc region of immunoglobulins, such as FCGR1A and FCGR2A, but also CSF3R, PLAUR, the receptors for IFNG, IL2, IL6 and IL8, and integrins, such as ITGB1 and ITGB2. During the phagocytic process, mediates mobilization of secretory lysosomes, degranulation, and activation of NADPH oxidase to bring about the respiratory burst. Plays a role in the release of inflammatory molecules. Promotes reorganization of the actin cytoskeleton and actin polymerization, formation of podosomes and cell protrusions. Inhibits TP73-mediated transcription activation and TP73-mediated apoptosis. Phosphorylates CBL in response to activation of immunoglobulin gamma Fc region receptors. Phosphorylates ADAM15, BCR, ELMO1, FCGR2A, GAB1, GAB2, RAPGEF1, STAT5B, TP73, VAV1 and WAS
Specific Function: Atp binding
Gene Name: HCK
Uniprot ID: P08631
Uniprot Name: Tyrosine-protein kinase HCK
Molecular Weight: 59599.355 Da

References

Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]

Property	Measurement	pH	Temperature (°C)	References
IC 50 (nM)	89	N/A	N/A	A30072
IC 50 (nM)	44	N/A	N/A	A30073 / A30078
IC 50 (nM)	17	N/A	N/A	A30073 / A30078
IC 50 (nM)	47	N/A	N/A	A30074
IC 50 (nM)	250	N/A	N/A	A29883
IC 50 (nM)	220	N/A	N/A	A29883
IC 50 (nM)	4	N/A	N/A	A28079
IC 50 (nM)	20	N/A	N/A	A30080
IC 50 (nM)	8	N/A	N/A	A30081
IC 50 (nM)	10	N/A	N/A	A30082
Kd (nM)	0.1	7	23	A29880 / A29882
Kd (nM)	0.098	N/A	N/A	A29881 / A30076
Kd (nM)	0.24	N/A	N/A	A27739
Kd (nM)	0.37	N/A	N/A	A28055
Kd (nM)	0.1	N/A	N/A	A30075
Kd (nM)	0.16	N/A	N/A	A30077
Kd (nM)	1	N/A	N/A	A30079
Kd (nM)	0.45	N/A	N/A	A28058
Kd (nM)	7.5	N/A	N/A	A30081
Kd (nM)	12	N/A	N/A	A30083
Kd (nM)	370	N/A	N/A	A18427
Ki (nM)	0.097	N/A	N/A	A28077
Ki (nM)	6.4	N/A	N/A	A30074
Ki (nM)	22	N/A	N/A	A30076

Details2. Mitogen-activated protein kinase 14

Kind: Protein
Organism: Humans
Pharmacological action: Unknown

General Function: Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK14 is one of the four p38 MAPKs which play an important role in the cascades of cellular responses evoked by extracellular stimuli such as pro-inflammatory cytokines or physical stress leading to direct activation of transcription factors. Accordingly, p38 MAPKs phosphorylate a broad range of proteins and it has been estimated that they may have approximately 200 to 300 substrates each. Some of the targets are downstream kinases which are activated through phosphorylation and further phosphorylate additional targets. RPS6KA5/MSK1 and RPS6KA4/MSK2 can directly phosphorylate and activate transcription factors such as CREB1, ATF1, the NF-kappa-B isoform RELA/NFKB3, STAT1 and STAT3, but can also phosphorylate histone H3 and the nucleosomal protein HMGN1 (PubMed:9687510, PubMed:9792677). RPS6KA5/MSK1 and RPS6KA4/MSK2 play important roles in the rapid induction of immediate-early genes in response to stress or mitogenic stimuli, either by inducing chromatin remodeling or by recruiting the transcription machinery (PubMed:9687510, PubMed:9792677). On the other hand, two other kinase targets, MAPKAPK2/MK2 and MAPKAPK3/MK3, participate in the control of gene expression mostly at the post-transcriptional level, by phosphorylating ZFP36 (tristetraprolin) and ELAVL1, and by regulating EEF2K, which is important for the elongation of mRNA during translation. MKNK1/MNK1 and MKNK2/MNK2, two other kinases activated by p38 MAPKs, regulate protein synthesis by phosphorylating the initiation factor EIF4E2 (PubMed:11154262). MAPK14 interacts also with casein kinase II, leading to its activation through autophosphorylation and further phosphorylation of TP53/p53 (PubMed:10747897). In the cytoplasm, the p38 MAPK pathway is an important regulator of protein turnover. For example, CFLAR is an inhibitor of TNF-induced apoptosis whose proteasome-mediated degradation is regulated by p38 MAPK phosphorylation. In a similar way, MAPK14 phosphorylates the ubiquitin ligase SIAH2, regulating its activity towards EGLN3 (PubMed:17003045). MAPK14 may also inhibit the lysosomal degradation pathway of autophagy by interfering with the intracellular trafficking of the transmembrane protein ATG9 (PubMed:19893488). Another function of MAPK14 is to regulate the endocytosis of membrane receptors by different mechanisms that impinge on the small GTPase RAB5A. In addition, clathrin-mediated EGFR internalization induced by inflammatory cytokines and UV irradiation depends on MAPK14-mediated phosphorylation of EGFR itself as well as of RAB5A effectors (PubMed:16932740). Ectodomain shedding of transmembrane proteins is regulated by p38 MAPKs as well. In response to inflammatory stimuli, p38 MAPKs phosphorylate the membrane-associated metalloprotease ADAM17 (PubMed:20188673). Such phosphorylation is required for ADAM17-mediated ectodomain shedding of TGF-alpha family ligands, which results in the activation of EGFR signaling and cell proliferation. Another p38 MAPK substrate is FGFR1. FGFR1 can be translocated from the extracellular space into the cytosol and nucleus of target cells, and regulates processes such as rRNA synthesis and cell growth. FGFR1 translocation requires p38 MAPK activation. In the nucleus, many transcription factors are phosphorylated and activated by p38 MAPKs in response to different stimuli. Classical examples include ATF1, ATF2, ATF6, ELK1, PTPRH, DDIT3, TP53/p53 and MEF2C and MEF2A (PubMed:10330143, PubMed:9430721, PubMed:9858528). The p38 MAPKs are emerging as important modulators of gene expression by regulating chromatin modifiers and remodelers. The promoters of several genes involved in the inflammatory response, such as IL6, IL8 and IL12B, display a p38 MAPK-dependent enrichment of histone H3 phosphorylation on 'Ser-10' (H3S10ph) in LPS-stimulated myeloid cells. This phosphorylation enhances the accessibility of the cryptic NF-kappa-B-binding sites marking promoters for increased NF-kappa-B recruitment. Phosphorylates CDC25B and CDC25C which is required for binding to 14-3-3 proteins and leads to initiation of a G2 delay after ultraviolet radiation (PubMed:11333986). Phosphorylates TIAR following DNA damage, releasing TIAR from GADD45A mRNA and preventing mRNA degradation (PubMed:20932473). The p38 MAPKs may also have kinase-independent roles, which are thought to be due to the binding to targets in the absence of phosphorylation. Protein O-Glc-N-acylation catalyzed by the OGT is regulated by MAPK14, and, although OGT does not seem to be phosphorylated by MAPK14, their interaction increases upon MAPK14 activation induced by glucose deprivation. This interaction may regulate OGT activity by recruiting it to specific targets such as neurofilament H, stimulating its O-Glc-N-acylation. Required in mid-fetal development for the growth of embryo-derived blood vessels in the labyrinth layer of the placenta. Also plays an essential role in developmental and stress-induced erythropoiesis, through regulation of EPO gene expression (PubMed:10943842). Isoform MXI2 activation is stimulated by mitogens and oxidative stress and only poorly phosphorylates ELK1 and ATF2. Isoform EXIP may play a role in the early onset of apoptosis. Phosphorylates S100A9 at 'Thr-113' (PubMed:15905572). Phosphorylates NLRP1 downstream of MAP3K20/ZAK in response to UV-B irradiation and ribosome collisions, promoting activation of the NLRP1 inflammasome and pyroptosis (PubMed:35857590)
Specific Function: Atp binding
Gene Name: MAPK14
Uniprot ID: Q16539
Uniprot Name: Mitogen-activated protein kinase 14
Molecular Weight: 41292.885 Da

References

Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [Article]
Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [Article]

Drug created at June 13, 2005 13:24 / Updated at August 26, 2024 19:21

Doramapimod

Identification

Structure for Doramapimod (DB03044)

Pharmacology

Interactions

Categories

Chemical Identifiers

References

Clinical Trials

Clinical Trial & Rare Diseases Add-on Data Package

Pharmacoeconomics

Properties

Spectra

Collision Cross Sections (CCS)

Targets

References

References