Target Information

Target General Information

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Target ID

T26500 (Former ID: TTDR01193)

Target Name

Histamine H4 receptor (H4R)

Synonyms

SP9144; Pfi-013; HH4R; H4 receptor; GPRv53; GPCR105; G protein-coupled receptor 105; AXOR35

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Gene Name

HRH4

Target Type

Clinical trial target

[1]

Disease

[+] 5 Target-related Diseases

Atopic eczema [ICD-11: EA80]

Psoriasis [ICD-11: EA90]

Rheumatoid arthritis [ICD-11: FA20]

Vasomotor/allergic rhinitis [ICD-11: CA08]

Asthma [ICD-11: CA23]

Function

Displays a significant level of constitutive activity (spontaneous activity in the absence of agonist). The H4 subclass of histamine receptors could mediate the histamine signals in peripheral tissues.

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BioChemical Class

GPCR rhodopsin

UniProt ID

HRH4_HUMAN

Sequence

MPDTNSTINLSLSTRVTLAFFMSLVAFAIMLGNALVILAFVVDKNLRHRSSYFFLNLAIS
DFFVGVISIPLYIPHTLFEWDFGKEICVFWLTTDYLLCTASVYNIVLISYDRYLSVSNAV
SYRTQHTGVLKIVTLMVAVWVLAFLVNGPMILVSESWKDEGSECEPGFFSEWYILAITSF
LEFVIPVILVAYFNMNIYWSLWKRDHLSRCQSHPGLTAVSSNICGHSFRGRLSSRRSLSA
STEVPASFHSERQRRKSSLMFSSRTKMNSNTIASKMGSFSQSDSVALHQREHVELLRARR
LAKSLAILLGVFAVCWAPYSLFTIVLSFYSSATGPKSVWYRIAFWLQWFNSFVNPLLYPL
CHKRFQKAFLKIFCIKKQPLPSQHSRSVSS

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3D Structure

Click to Show 3D Structure of This Target

AlphaFold

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 3 Clinical Trial Drugs

JNJ-38518168

Drug Info

Phase 2

Rheumatoid arthritis

[2]

PF-3893787

Drug Info

Phase 2

Atopic dermatitis

[3]

UR-63325

Drug Info

Phase 2

Allergic rhinitis

[4]

Discontinued Drug(s)

[+] 1 Discontinued Drugs

Thioperamide

Drug Info

Terminated

Cognitive impairment

[5], [6]

Mode of Action

[+] 3 Modes of Action

Antagonist

[+] 7 Antagonist drugs

JNJ-38518168

Drug Info

[7]

PF-3893787

Drug Info

[1]

UR-63325

Drug Info

[8]

Thioperamide

Drug Info

[9], [10], [11]

burimamide

Drug Info

[21]

JNJ-10191584

Drug Info

[27]

[3H]JNJ 7777120

Drug Info

[32], [33]

Inhibitor

[+] 10 Inhibitor drugs

(1H-indol-2-yl)(piperazin-1-yl)methanone

Drug Info

[12]

(R)-3-(1H-imidazol-4-yl)propyl sec-butylcarbamate

Drug Info

[13]

2-(2-(4-tert-Butylphenylthio)ethyl)-1H-imidazole

Drug Info

[16]

6-(4-Methylpiperazin-1-yl)-9H-purin-2-amine

Drug Info

[19]

6-(4-methylpiperazin-1-yl)-9Hpurine

Drug Info

[19]

6-(4-Methylpiperazin-1-yl)pyrimidine-2,4-diamine

Drug Info

[19]

9-benzyl-6-(4-methylpiperazin-1-yl)-9H-purine

Drug Info

[19]

A-846714

Drug Info

[20]

A-943931

Drug Info

[20]

[125I]iodophenpropit

Drug Info

[31]

Agonist

[+] 17 Agonist drugs

(R)-alpha-methylhistamine

Drug Info

[14]

(S)-alpha-methylhistamine

Drug Info

[15]

2-(3-bromophenyl)histamine

Drug Info

[17]

2-methylhistamine

Drug Info

[18]

4-methylhistamine

Drug Info

[18]

Clobenpropit

Drug Info

[22], [23]

HTMT

Drug Info

[24]

Imetit

Drug Info

[25], [26]

improgan

Drug Info

[24]

impromidine

Drug Info

[17]

N,N-dimethylhistamine

Drug Info

[18]

N-ethylhistamine

Drug Info

[18]

N-methylhistamine

Drug Info

[21]

N-[3H]alpha-methylhistamine

Drug Info

[28]

N-[3H]methylhistamine

Drug Info

[14]

UR-60427

Drug Info

[29]

VUF 8430

Drug Info

[30]

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Different Human System Profiles of Target	Top
Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target. A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020). Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function. Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006). Human Similarity Proteins Human Pathway Affiliation

Different Human System Profiles of Target

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Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.

A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020).

Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.

Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006).

Human Similarity Proteins

Human Pathway Affiliation

Protein Name	Pfam ID	Percentage of Identity (%)	E value
Putative olfactory receptor 3A4 (OR3A4P)	PF13853	25.806 (32/124)	1.36E-05
Olfactory receptor 14I1 (OR14I1)	PF13853	28.448 (33/116)	7.20E-05
Olfactory receptor 11A1 (OR11A1)	PF13853	26.027 (38/146)	1.10E-04
Olfactory receptor 4K2 (OR4K2)	PF13853	29.167 (42/144)	1.42E-04
Olfactory receptor 4K15 (OR4K15)	PF13853	29.927 (41/137)	1.59E-04
Olfactory receptor 10G7 (OR10G7)	PF13853	31.068 (32/103)	1.85E-04
Olfactory receptor 2F1 (OR2F1)	PF13853	30.657 (42/137)	2.10E-04
Olfactory receptor 4D9 (OR4D9)	PF13853	30.370 (41/135)	2.46E-04
Olfactory receptor 10G4 (OR10G4)	PF13853	30.172 (35/116)	3.13E-04
Olfactory receptor 1M1 (OR1M1)	PF13853	26.543 (43/162)	3.63E-04
Olfactory receptor 3A3 (OR3A3)	PF13853	26.772 (34/127)	3.91E-04
Olfactory receptor 10G9 (OR10G9)	PF13853	30.097 (31/103)	4.51E-04
Olfactory receptor 4E2 (OR4E2)	PF13853	28.440 (31/109)	5.71E-04
Olfactory receptor 14A2 (OR14A2)	PF13853	25.000 (40/160)	6.66E-04
Olfactory receptor 5V1 (OR5V1)	PF13853	25.000 (55/220)	6.96E-04
Olfactory receptor 13H1 (OR13H1)	PF13853	26.718 (35/131)	1.00E-03
Olfactory receptor 4D1 (OR4D1)	PF13853	29.661 (35/118)	1.00E-03
Olfactory receptor 1A2 (OR1A2)	PF13853	26.389 (38/144)	2.00E-03
Olfactory receptor 4E1 (OR4E1)	PF13853	24.793 (30/121)	2.00E-03
Olfactory receptor 1D2 (OR1D2)	PF13853	29.801 (45/151)	2.00E-03
Olfactory receptor 2S2 (OR2S2)	PF13853	26.733 (27/101)	2.00E-03
Olfactory receptor 4K14 (OR4K14)	PF13853	28.800 (36/125)	2.00E-03
Olfactory receptor 10G3 (OR10G3)	PF13853	28.148 (38/135)	2.00E-03
Olfactory receptor 4K3 (OR4K3)	PF13853	28.859 (43/149)	3.00E-03
Olfactory receptor 2D3 (OR2D3)	PF13853	30.252 (36/119)	3.00E-03
Olfactory receptor 10G8 (OR10G8)	PF13853	28.155 (29/103)	3.00E-03
Olfactory receptor 13J1 (OR13J1)	PF13853	28.814 (34/118)	4.00E-03
Olfactory receptor 10G2 (OR10G2)	PF13853	29.167 (35/120)	4.00E-03
Olfactory receptor 3A2 (OR3A2)	PF13853	26.852 (29/108)	4.00E-03
Putative olfactory receptor 14L1 (OR14L1P)	PF13853	28.846 (30/104)	5.00E-03
Click to Show/Hide the Information of Human Similarity Proteins

KEGG Pathway	Pathway ID	Affiliated Target	Pathway Map
Neuroactive ligand-receptor interaction	hsa04080	Affiliated Target
Class: Environmental Information Processing => Signaling molecules and interaction	Pathway Hierarchy

Chemical Structure based Activity Landscape of Target

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Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Co-Targets

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Co-Targets

Co-Targets Info

Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Profiles in Patients

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Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways

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KEGG Pathway

[+] 1 KEGG Pathways

Neuroactive ligand-receptor interaction

Reactome

[+] 2 Reactome Pathways

Histamine receptors

G alpha (i) signalling events

WikiPathways

[+] 3 WikiPathways

GPCR ligand binding

GPCR downstream signaling

GPCRs, Other

Target-Related Models and Studies

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Target Validation

Target Validation Info

Target QSAR Model

References

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REF 1

Challenges of drug discovery in novel target space. The discovery and evaluation of PF-3893787: a novel histamine H4 receptor antagonist. Bioorg Med Chem Lett. 2011 Nov 1;21(21):6596-602.

REF 2

ClinicalTrials.gov (NCT02295865) A Study to Evaluate Safety and Efficacy of Toreforant (JNJ-38518168) in Participants With Moderate to Severe Plaque-type Psoriasis. U.S. National Institutes of Health.

REF 3

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 4

ClinicalTrials.gov (NCT01260753) Proof of Activity Study of UR-63325 in Allergic Rhinitis Induced by Nasal Challenge. U.S. National Institutes of Health.

REF 5

URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 1267).

REF 6

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800004362)

REF 7

The histamine H4 receptor: from orphan to the clinic. Front Pharmacol. 2015; 6: 65.

REF 8

Azines as histamine H4 receptor antagonists. Front Biosci (Schol Ed). 2012 Jan 1;4:967-87.

REF 9

Role of histamine in short- and long-term effects of methamphetamine on the developing mouse brain. J Neurochem. 2008 Nov;107(4):976-86.

REF 10

Role of histamine H3 and H4 receptors in mechanical hyperalgesia following peripheral nerve injury. Neuroimmunomodulation. 2007;14(6):317-25.

REF 11

The histamine H3 receptor: from gene cloning to H3 receptor drugs. Nat Rev Drug Discov. 2005 Feb;4(2):107-20.

REF 12

Preparation and biological evaluation of indole, benzimidazole, and thienopyrrole piperazine carboxamides: potent human histamine h(4) antagonists. J Med Chem. 2005 Dec 29;48(26):8289-98.

REF 13

Histamine H3 and H4 receptor affinity of branched 3-(1H-imidazol-4-yl)propyl N-alkylcarbamates. Bioorg Med Chem Lett. 2009 Dec 1;19(23):6682-5.

REF 14

Cloning and pharmacological characterization of a fourth histamine receptor (H(4)) expressed in bone marrow. Mol Pharmacol. 2001 Mar;59(3):420-6.

REF 15

Cloning and characterization of a novel human histamine receptor. J Pharmacol Exp Ther. 2001 Mar;296(3):1058-66.

REF 16

Synthesis and structure-activity relationships of N-aryl-piperidine derivatives as potent (partial) agonists for human histamine H3 receptor. Bioorg Med Chem. 2010 Jul 15;18(14):5441-8.

REF 17

Evaluation of histamine H1-, H2-, and H3-receptor ligands at the human histamine H4 receptor: identification of 4-methylhistamine as the first pote... J Pharmacol Exp Ther. 2005 Sep;314(3):1310-21.

REF 18

Compared pharmacology of human histamine H3 and H4 receptors: structure-activity relationships of histamine derivatives. Br J Pharmacol. 2006 Apr;147(7):744-54.

REF 19

2,4-Diaminopyrimidines as histamine H4 receptor ligands--Scaffold optimization and pharmacological characterization. Bioorg Med Chem. 2009 Oct 15;17(20):7186-96.

REF 20

Rotationally constrained 2,4-diamino-5,6-disubstituted pyrimidines: a new class of histamine H4 receptor antagonists with improved druglikeness and... J Med Chem. 2008 Oct 23;51(20):6547-57.

REF 21

Comparison of human, mouse, rat, and guinea pig histamine H4 receptors reveals substantial pharmacological species variation. J Pharmacol Exp Ther. 2001 Oct;299(1):121-30.

REF 22

Clobenpropit analogs as dual activity ligands for the histamine H3 and H4 receptors: synthesis, pharmacological evaluation, and cross-target QSAR s... Bioorg Med Chem. 2009 Jun 1;17(11):3987-94.

REF 23

The histamine H4 receptor is functionally expressed on T(H)2 cells. J Allergy Clin Immunol. 2009 Mar;123(3):619-25.

REF 24

Cloning, expression, and pharmacological characterization of a novel human histamine receptor. Mol Pharmacol. 2001 Mar;59(3):434-41.

REF 25

Histamine excites neonatal rat sympathetic preganglionic neurons in vitro via activation of H1 receptors. J Neurophysiol. 2006 Apr;95(4):2492-500.

REF 26

Histamine H4 receptor mediates eosinophil chemotaxis with cell shape change and adhesion molecule upregulation. Br J Pharmacol. 2004 May;142(1):161-71.

REF 27

Synthesis and structure-activity relationships of indole and benzimidazole piperazines as histamine H(4) receptor antagonists. Bioorg Med Chem Lett. 2004 Nov 1;14(21):5251-6.

REF 28

Histamine induces cytoskeletal changes in human eosinophils via the H(4) receptor. Br J Pharmacol. 2003 Nov;140(6):1117-27.

REF 29

REF 30

Discovery of S-(2-guanidylethyl)-isothiourea (VUF 8430) as a potent nonimidazole histamine H4 receptor agonist. J Med Chem. 2006 Nov 16;49(23):6650-1.

REF 31

Discovery of novel human histamine H4 receptor ligands by large-scale structure-based virtual screening. J Med Chem. 2008 Jun 12;51(11):3145-53.

REF 32

A potent and selective histamine H4 receptor antagonist with anti-inflammatory properties. J Pharmacol Exp Ther. 2004 Apr;309(1):404-13.

REF 33

Identification and hit-to-lead exploration of a novel series of histamine H4 receptor inverse agonists. Bioorg Med Chem Lett. 2010 Apr 15;20(8):2516-9.

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