Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTXJ178)

• DTT Name: Histamine H4 receptor (H4R)
• Synonyms: SP9144; Pfi-013; HH4R; H4 receptor; GPRv53; GPCR105; G protein-coupled receptor 105; AXOR35
• Gene Name: HRH4
• DTT Type: Clinical trial target; [1]
• BioChemical Class: GPCR rhodopsin
• UniProt ID: HRH4_HUMAN
• TTD ID: T26500
• Sequence:
  MPDTNSTINLSLSTRVTLAFFMSLVAFAIMLGNALVILAFVVDKNLRHRSSYFFLNLAIS
  DFFVGVISIPLYIPHTLFEWDFGKEICVFWLTTDYLLCTASVYNIVLISYDRYLSVSNAV
  SYRTQHTGVLKIVTLMVAVWVLAFLVNGPMILVSESWKDEGSECEPGFFSEWYILAITSF
  LEFVIPVILVAYFNMNIYWSLWKRDHLSRCQSHPGLTAVSSNICGHSFRGRLSSRRSLSA
  STEVPASFHSERQRRKSSLMFSSRTKMNSNTIASKMGSFSQSDSVALHQREHVELLRARR
  LAKSLAILLGVFAVCWAPYSLFTIVLSFYSSATGPKSVWYRIAFWLQWFNSFVNPLLYPL
  CHKRFQKAFLKIFCIKKQPLPSQHSRSVSS
• 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.
• KEGG Pathway: Neuroactive ligand-receptor interaction (hsa04080)
• Reactome Pathway:
  G alpha (i) signalling events (R-HSA-418594)
  Histamine receptors (R-HSA-390650)

Molecular Interaction Atlas (MIA) of This DTT

3 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
JNJ-38518168	DM9UMIO	Plaque psoriasis	EA90.0	Phase 2	[2]
PF-3893787	DMC2FAL	Atopic dermatitis	EA80	Phase 2	[1]
UR-63325	DME6X27	Allergic rhinitis	CA08.0	Phase 2	[3]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Thioperamide	DM8S593	Cognitive impairment	6D71	Terminated	[4]

30 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(1H-indol-2-yl)(piperazin-1-yl)methanone	DMW15DS	Discovery agent	N.A.	Investigative	[5]
(R)-3-(1H-imidazol-4-yl)propyl sec-butylcarbamate	DMCSHI3	Discovery agent	N.A.	Investigative	[6]
(R)-alpha-methylhistamine	DMKAW4P	Discovery agent	N.A.	Investigative	[7]
(S)-alpha-methylhistamine	DMTUZIN	Discovery agent	N.A.	Investigative	[8]
2-(2-(4-tert-Butylphenylthio)ethyl)-1H-imidazole	DMZVBPG	Discovery agent	N.A.	Investigative	[9]
2-(3-bromophenyl)histamine	DM260RG	Discovery agent	N.A.	Investigative	[10]
2-methylhistamine	DMD8CQS	Discovery agent	N.A.	Investigative	[11]
4-methylhistamine	DMABMPQ	Discovery agent	N.A.	Investigative	[11]
6-(4-Methylpiperazin-1-yl)-9H-purin-2-amine	DMWITYU	Discovery agent	N.A.	Investigative	[12]
6-(4-methylpiperazin-1-yl)-9Hpurine	DMA3FQP	Discovery agent	N.A.	Investigative	[12]
6-(4-Methylpiperazin-1-yl)pyrimidine-2,4-diamine	DMYAS2V	Discovery agent	N.A.	Investigative	[12]
9-benzyl-6-(4-methylpiperazin-1-yl)-9H-purine	DM4JG60	Discovery agent	N.A.	Investigative	[12]
A-846714	DM5TDEW	Discovery agent	N.A.	Investigative	[13]
A-943931	DMROD7Q	Discovery agent	N.A.	Investigative	[13]
burimamide	DMZ2VYG	Discovery agent	N.A.	Investigative	[14]
Clobenpropit	DM537OH	Discovery agent	N.A.	Investigative	[15]
HTMT	DMPT8JN	Discovery agent	N.A.	Investigative	[16]
Imetit	DMMJ6NS	Discovery agent	N.A.	Investigative	[17]
improgan	DMQ4ICU	Discovery agent	N.A.	Investigative	[16]
impromidine	DMTDRPM	Discovery agent	N.A.	Investigative	[10]
JNJ-10191584	DM6P1UA	Discovery agent	N.A.	Investigative	[18]
N,N-dimethylhistamine	DM8WPD2	Discovery agent	N.A.	Investigative	[11]
N-ethylhistamine	DMYI87T	Discovery agent	N.A.	Investigative	[11]
N-methylhistamine	DMCFH5W	Discovery agent	N.A.	Investigative	[14]
N-[3H]alpha-methylhistamine	DMWDCV1	Discovery agent	N.A.	Investigative	[19]
N-[3H]methylhistamine	DM0CI4L	Discovery agent	N.A.	Investigative	[7]
UR-60427	DM3YE5X	Asthma	CA23	Investigative	[20]
VUF 8430	DMJC0UH	Discovery agent	N.A.	Investigative	[21]
[125I]iodophenpropit	DMN4ABU	Discovery agent	N.A.	Investigative	[22]
[3H]JNJ 7777120	DMZT8UD	Inflammation	1A00-CA43.1	Investigative	[23]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Rheumatoid arthritis	FA20	Synovial tissue	1.32E-01	0.1	0.9
Asthma	CA23	Nasal and bronchial airway	3.67E-01	-0.05	-0.18

References

• [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.
• [2] The histamine H4 receptor: from orphan to the clinic. Front Pharmacol. 2015; 6: 65.
• [3] Azines as histamine H4 receptor antagonists. Front Biosci (Schol Ed). 2012 Jan 1;4:967-87.
• [4] Role of histamine in short- and long-term effects of methamphetamine on the developing mouse brain. J Neurochem. 2008 Nov;107(4):976-86.
• [5] 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.
• [6] 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.
• [7] Cloning and pharmacological characterization of a fourth histamine receptor (H(4)) expressed in bone marrow. Mol Pharmacol. 2001 Mar;59(3):420-6.
• [8] Cloning and characterization of a novel human histamine receptor. J Pharmacol Exp Ther. 2001 Mar;296(3):1058-66.
• [9] 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.
• [10] 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.
• [11] Compared pharmacology of human histamine H3 and H4 receptors: structure-activity relationships of histamine derivatives. Br J Pharmacol. 2006 Apr;147(7):744-54.
• [12] 2,4-Diaminopyrimidines as histamine H4 receptor ligands--Scaffold optimization and pharmacological characterization. Bioorg Med Chem. 2009 Oct 15;17(20):7186-96.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] Cloning, expression, and pharmacological characterization of a novel human histamine receptor. Mol Pharmacol. 2001 Mar;59(3):434-41.
• [17] Histamine excites neonatal rat sympathetic preganglionic neurons in vitro via activation of H1 receptors. J Neurophysiol. 2006 Apr;95(4):2492-500.
• [18] 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.
• [19] Histamine induces cytoskeletal changes in human eosinophils via the H(4) receptor. Br J Pharmacol. 2003 Nov;140(6):1117-27.
• [20] 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).
• [21] 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.
• [22] 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.
• [23] A potent and selective histamine H4 receptor antagonist with anti-inflammatory properties. J Pharmacol Exp Ther. 2004 Apr;309(1):404-13.