Target Information
| Target General Information | Top | |||||
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| Target ID |
T26500
(Former ID: TTDR01193)
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| Target Name |
Histamine H4 receptor (H4R)
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| Synonyms |
SP9144; Pfi-013; HH4R; H4 receptor; GPRv53; GPCR105; G protein-coupled receptor 105; AXOR35
Click to Show/Hide
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| Gene Name |
HRH4
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 5 Target-related Diseases | + | ||||
| 1 | Atopic eczema [ICD-11: EA80] | |||||
| 2 | Psoriasis [ICD-11: EA90] | |||||
| 3 | Rheumatoid arthritis [ICD-11: FA20] | |||||
| 4 | Vasomotor/allergic rhinitis [ICD-11: CA08] | |||||
| 5 | 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
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| UniProt ID | ||||||
| Sequence |
MPDTNSTINLSLSTRVTLAFFMSLVAFAIMLGNALVILAFVVDKNLRHRSSYFFLNLAIS
DFFVGVISIPLYIPHTLFEWDFGKEICVFWLTTDYLLCTASVYNIVLISYDRYLSVSNAV SYRTQHTGVLKIVTLMVAVWVLAFLVNGPMILVSESWKDEGSECEPGFFSEWYILAITSF LEFVIPVILVAYFNMNIYWSLWKRDHLSRCQSHPGLTAVSSNICGHSFRGRLSSRRSLSA STEVPASFHSERQRRKSSLMFSSRTKMNSNTIASKMGSFSQSDSVALHQREHVELLRARR LAKSLAILLGVFAVCWAPYSLFTIVLSFYSSATGPKSVWYRIAFWLQWFNSFVNPLLYPL CHKRFQKAFLKIFCIKKQPLPSQHSRSVSS Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 3 Clinical Trial Drugs | + | ||||
| 1 | JNJ-38518168 | Drug Info | Phase 2 | Rheumatoid arthritis | [2] | |
| 2 | PF-3893787 | Drug Info | Phase 2 | Atopic dermatitis | [3] | |
| 3 | UR-63325 | Drug Info | Phase 2 | Allergic rhinitis | [4] | |
| Discontinued Drug(s) | [+] 1 Discontinued Drugs | + | ||||
| 1 | Thioperamide | Drug Info | Terminated | Cognitive impairment | [5], [6] | |
| Mode of Action | [+] 3 Modes of Action | + | ||||
| Antagonist | [+] 7 Antagonist drugs | + | ||||
| 1 | JNJ-38518168 | Drug Info | [7] | |||
| 2 | PF-3893787 | Drug Info | [1] | |||
| 3 | UR-63325 | Drug Info | [8] | |||
| 4 | Thioperamide | Drug Info | [9], [10], [11] | |||
| 5 | burimamide | Drug Info | [21] | |||
| 6 | JNJ-10191584 | Drug Info | [27] | |||
| 7 | [3H]JNJ 7777120 | Drug Info | [32], [33] | |||
| Inhibitor | [+] 9 Inhibitor drugs | + | ||||
| 1 | (1H-indol-2-yl)(piperazin-1-yl)methanone | Drug Info | [12] | |||
| 2 | (R)-3-(1H-imidazol-4-yl)propyl sec-butylcarbamate | Drug Info | [13] | |||
| 3 | 2-(2-(4-tert-Butylphenylthio)ethyl)-1H-imidazole | Drug Info | [16] | |||
| 4 | 6-(4-Methylpiperazin-1-yl)-9H-purin-2-amine | Drug Info | [19] | |||
| 5 | 6-(4-methylpiperazin-1-yl)-9Hpurine | Drug Info | [19] | |||
| 6 | 9-benzyl-6-(4-methylpiperazin-1-yl)-9H-purine | Drug Info | [19] | |||
| 7 | A-846714 | Drug Info | [20] | |||
| 8 | A-943931 | Drug Info | [20] | |||
| 9 | [125I]iodophenpropit | Drug Info | [31] | |||
| Agonist | [+] 17 Agonist drugs | + | ||||
| 1 | (R)-alpha-methylhistamine | Drug Info | [14] | |||
| 2 | (S)-alpha-methylhistamine | Drug Info | [15] | |||
| 3 | 2-(3-bromophenyl)histamine | Drug Info | [17] | |||
| 4 | 2-methylhistamine | Drug Info | [18] | |||
| 5 | 4-methylhistamine | Drug Info | [18] | |||
| 6 | Clobenpropit | Drug Info | [22], [23] | |||
| 7 | HTMT | Drug Info | [24] | |||
| 8 | Imetit | Drug Info | [25], [26] | |||
| 9 | improgan | Drug Info | [24] | |||
| 10 | impromidine | Drug Info | [17] | |||
| 11 | N,N-dimethylhistamine | Drug Info | [18] | |||
| 12 | N-ethylhistamine | Drug Info | [18] | |||
| 13 | N-methylhistamine | Drug Info | [21] | |||
| 14 | N-[3H]alpha-methylhistamine | Drug Info | [28] | |||
| 15 | N-[3H]methylhistamine | Drug Info | [14] | |||
| 16 | UR-60427 | Drug Info | [29] | |||
| 17 | VUF 8430 | Drug Info | [30] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Different Human System Profiles of Target | Top |
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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
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| Neuroactive ligand-receptor interaction | hsa04080 | Affiliated Target |
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| Class: Environmental Information Processing => Signaling molecules and interaction | Pathway Hierarchy | ||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "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 | Top | |||||
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| Co-Targets | ||||||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 1 KEGG Pathways | + | ||||
| 1 | Neuroactive ligand-receptor interaction | |||||
| Reactome | [+] 2 Reactome Pathways | + | ||||
| 1 | Histamine receptors | |||||
| 2 | G alpha (i) signalling events | |||||
| WikiPathways | [+] 3 WikiPathways | + | ||||
| 1 | GPCR ligand binding | |||||
| 2 | GPCR downstream signaling | |||||
| 3 | GPCRs, Other | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| Target QSAR Model | ||||||
| References | Top | |||||
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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 | 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. (Target id: 265). | |||||
| 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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