Target Validation Information
TTD ID T64765
Target Name Histamine H3 receptor (H3R)
Type of Target
Successful
Drug Potency against Target ABT-239 Drug Info Ki = 0.45 nM [31]
Cipralisant Drug Info Ki = 5.25 nM [30]
Drug Info Ki = 42.2 nM [3]
(1H-indol-2-yl)(piperazin-1-yl)methanone Drug Info Ki = 9000 nM [7]
(1R,2R)-2-(1H-Imidazol-4-yl)-1-methyl-propylamine Drug Info Ki = 11 nM [27]
(1R,2S)-2-(1H-Imidazol-4-yl)-1-methyl-propylamine Drug Info Ki = 0.8 nM [27]
(1S,2S)-2-(1H-Imidazol-4-yl)-cyclopentylamine Drug Info Ki = 740 nM [27]
(R)-1-(2-methoxyphenethyl)-2-methylpyrrolidine Drug Info Ki = 110 nM [10]
(R)-1-(3-methoxyphenethyl)-2-methylpyrrolidine Drug Info Ki = 160 nM [10]
(R)-1-(4-methoxyphenethyl)-2-methylpyrrolidine Drug Info Ki = 12 nM [10]
(R)-1-(4-nitrophenethyl)-2-methylpyrrolidine Drug Info Ki = 280 nM [10]
(R)-2-(2-(2-methylpyrrolidin-1-yl)ethyl)phenol Drug Info Ki = 240 nM [10]
(R)-2-(2-(2-methylpyrrolidin-1-yl)ethyl)pyridine Drug Info Ki = 200 nM [10]
(R)-2-methyl-1-(2-m-tolyl-ethyl)-pyrrolidine Drug Info Ki = 30 nM [10]
(R)-2-methyl-1-(2-p-tolyl-ethyl)-pyrrolidine Drug Info Ki = 37 nM [10]
(R)-3-(1H-imidazol-4-yl)propyl sec-butylcarbamate Drug Info Ki = 19 nM [20]
(R)-3-(2-(2-methylpyrrolidin-1-yl)ethyl)pyridine Drug Info Ki = 320 nM [10]
(R)-4-(2-(2-methylpyrrolidin-1-yl)ethyl)pyridine Drug Info Ki = 320 nM [10]
(R)-6-(2-(2-methylpyrrolidin-1-yl)ethyl)quinoline Drug Info Ki = 41 nM [22]
(S)-1-(2-methoxyphenethyl)-2-methylpyrrolidine Drug Info Ki = 240 nM [10]
(S)-1-(3-methoxyphenethyl)-2-methylpyrrolidine Drug Info Ki = 170 nM [10]
(S)-1-(4-methoxyphenethyl)-2-methylpyrrolidine Drug Info Ki = 63 nM [10]
(S)-1-(4-nitrophenethyl)-2-methylpyrrolidine Drug Info Ki = 260 nM [10]
(S)-2-(2-(2-methylpyrrolidin-1-yl)ethyl)phenol Drug Info Ki = 220 nM [10]
(S)-2-(2-(2-methylpyrrolidin-1-yl)ethyl)pyridine Drug Info Ki = 340 nM [10]
(S)-2-methyl-1-(2-m-tolyl-ethyl)-pyrrolidine Drug Info Ki = 240 nM [10]
(S)-2-methyl-1-(2-p-tolyl-ethyl)-pyrrolidine Drug Info Ki = 330 nM [10]
(S)-3-(1H-imidazol-4-yl)propyl sec-butylcarbamate Drug Info Ki = 23 nM [20]
(S)-4-(2-(2-methylpyrrolidin-1-yl)ethyl)pyridine Drug Info Ki = 140 nM [10]
1-(2-(naphthalen-2-yl)ethyl)pyrrolidine Drug Info Ki = 30 nM [10]
1-(2-m-tolyl-ethyl)-pyrrolidine Drug Info Ki = 200 nM [10]
1-(2-methoxyphenethyl)pyrrolidine Drug Info Ki = 260 nM [10]
1-(2-p-tolyl-ethyl)-pyrrolidine Drug Info Ki = 81 nM [10]
1-(3-(2-(3-methoxyphenoxy)ethoxy)propyl)azepane Drug Info Ki = 62 nM [16]
1-(3-(3-phenylpropoxy)propyl)piperidine Drug Info Ki = 3.1 nM [13]
1-(3-(4-(2-fluoroethyl)phenoxy)propyl)piperidine Drug Info Ki = 43 nM [15]
1-(3-(4-(fluoromethyl)phenoxy)propyl)piperidine Drug Info Ki = 17.3 nM [15]
1-(3-methoxyphenethyl)pyrrolidine Drug Info Ki = 260 nM [10]
1-(4-(benzyloxy)phenethyl)pyrrolidine Drug Info Ki = 40 nM [10]
1-(4-methoxyphenethyl)pyrrolidine Drug Info Ki = 370 nM [10]
1-(4-nitrophenethyl)pyrrolidine Drug Info Ki = 360 nM [10]
1-[2-(2,4,6-trimethyl-phenyl)-ethyl]-pyrrolidine Drug Info Ki = 230 nM [10]
2-((1H-imidazol-4-yl)methyl)pyridine Drug Info Ki = 1800 nM [24]
2-((2-ethoxyphenoxy)methyl)-4-isopropylmorpholine Drug Info Ki = 9000 nM [14]
2-(1,4'-bipiperidin-1'-yl)thiazolo[4,5-b]pyridine Drug Info Ki = 139 nM [19]
2-(1,4'-bipiperidin-1'-yl)thiazolo[4,5-c]pyridine Drug Info Ki = 128 nM [19]
2-(2-(4-tert-Butylphenylthio)ethyl)-1H-imidazole Drug Info Ki = 0.43 nM [24]
2-(2-(pyrrolidin-1-yl)ethyl)-1H-indole Drug Info Ki = 219 nM [10]
2-(2-(pyrrolidin-1-yl)ethyl)phenol Drug Info Ki = 340 nM [10]
2-(2-(pyrrolidin-1-yl)ethyl)pyridine Drug Info Ki = 320 nM [10]
2-(3-Methyl-3H-imidazol-4-yl)-ethylamine Drug Info Ki = 1 nM [28]
2-(4-Cyclopentyl-piperazin-1-yl)-quinoline Drug Info Ki = 28 nM [4]
2-(4-Cyclopropyl-piperazin-1-yl)-quinoline Drug Info Ki = 13 nM [4]
2-(4-Isopropyl-piperazin-1-yl)-quinoline Drug Info Ki = 6.8 nM [4]
2-(4-Methyl-piperazin-1-yl)-quinoline Drug Info Ki = 410 nM [4]
2-(4-Propyl-piperazin-1-yl)-quinoline Drug Info Ki = 6 nM [4]
2-(ethoxycarbonyl)-1H-indole-5-carboxylic acid Drug Info Ki = 7 nM [17]
2-[4-(1-Ethyl-propyl)-piperazin-1-yl]-quinoline Drug Info Ki = 2.9 nM [4]
3-((1H-imidazol-4-yl)methyl)pyridine Drug Info Ki = 76 nM [24]
4-((1H-imidazol-4-yl)methyl)-1-heptylpiperidine Drug Info Ki = 2 nM [5]
4-((1H-Imidazol-4-yl)methyl)-1-phenylpiperidine Drug Info Ki = 30 nM
4-((2R,3S)-2-Methyl-pyrrolidin-3-yl)-1H-imidazole Drug Info Ki = 8.7 nM [27]
4-((2S,3R)-2-Methyl-pyrrolidin-3-yl)-1H-imidazole Drug Info Ki = 33 nM [27]
4-(2-(3,4-Dimethylphenylamino)ethyl)-1H-imidazole Drug Info Ki = 9.9 nM [21]
4-(2-(3-tert-Butylphenylamino)ethyl)-1H-imidazole Drug Info Ki = 2.2 nM [21]
4-(2-(4-Cyclohexylphenylamino)ethyl)-1H-imidazole Drug Info Ki = 4.1 nM [21]
4-(2-(4-Methoxyphenylamino)ethyl)-1H-imidazole Drug Info Ki = 24 nM [21]
4-(2-(4-Methylphenylamino)ethyl)-1H-imidazole Drug Info Ki = 14 nM [21]
4-(2-(4-tert-Butylphenylamino)ethyl)-1H-imidazole Drug Info Ki = 0.89 nM [21]
4-(2-(Cyclohexylamino)ethyl)-1H-imidazole Drug Info Ki = 1600 nM [21]
4-(2-(Phenylamino)ethyl)-1H-imidazole Drug Info Ki = 56 nM [21]
4-(2-(pyrrolidin-1-yl)ethyl)pyridine Drug Info Ki = 320 nM [10]
4-(3-Phenoxy-propyl)-1H-imidazole Drug Info Ki = 4.9 nM [2]
4-(4-butylpiperidin-1-yl)-1-o-tolylbutan-1-one Drug Info Ki < 1000 nM [23]
4-(6-Cyclohexyl-hex-3-ynyl)-1H-imidazole Drug Info Ki = 2.9 nM [28]
4-(6-Cyclopentyl-hex-3-ynyl)-1H-imidazole Drug Info Ki = 0.95 nM [28]
4-(7,7-Dimethyl-oct-3-ynyl)-1H-imidazole Drug Info Ki = 0.8 nM [28]
4-(7-Methyl-oct-3-ynyl)-1H-imidazole Drug Info Ki = 3.7 nM [28]
4-(8-Phenyl-oct-3-ynyl)-1H-imidazole Drug Info Ki = 3.5 nM [28]
4-Benzyl-1-[3-phenylpropoxy)propyl]piperidine Drug Info Ki = 326 nM [13]
4-Butyl-1-[3-(phenylpropoxy)propyl]piperidine Drug Info Ki = 274 nM [13]
4-Hept-3-ynyl-1H-imidazole Drug Info Ki = 27 nM [28]
4-Hex-3-ynyl-1H-imidazole Drug Info Ki = 79 nM [28]
4-isopropyl-2-(phenoxymethyl)morpholine Drug Info Ki = 4800 nM [14]
4-Propyl-1-[3-(phenylpropoxy)propyl]piperidine Drug Info Ki = 249 nM [13]
4-[3-(4-Butyl-phenoxy)-propyl]-1H-imidazole Drug Info Ki = 60 nM [1]
4-[3-(4-Ethynyl-phenoxy)-propyl]-1H-imidazole Drug Info Ki = 2.3 nM [1]
4-[3-(4-Methoxy-phenoxy)-propyl]-1H-imidazole Drug Info Ki = 7.9 nM [2]
5-(2-(pyrrolidin-1-yl)ethyl)isothiazole Drug Info Ki = 190 nM [10]
5-ethyl-2-(2-(pyrrolidin-1-yl)ethyl)pyridine Drug Info Ki = 160 nM [10]
5-methoxy-2-(2-(pyrrolidin-1-yl)ethyl)-1H-indole Drug Info Ki = 230 nM [10]
5-phenyl-2-(4-(piperidin-1-yl)butyl)oxazole Drug Info Ki = 63 nM [25]
A-317920 Drug Info Ki = 12 nM [11]
Aerophobin-1 Drug Info IC50 = 9000 nM
APLYSAMINE Drug Info IC50 = 500 nM [12]
CARCININE Drug Info Ki = 294 nM [12]
CONESSINE Drug Info Ki = 24.5 nM [18]
Des-bromoaplysamine-1 Drug Info Ki = 89 nM [6]
FUB 349 Drug Info Ki = 12 nM [2]
GR-175737 Drug Info Ki = 7 nM [28]
GSK189254A Drug Info Ki = 0.26 nM [26]
GT-2016 Drug Info Ki = 40 nM [28]
IODOPROXYFAN Drug Info Ki = 71 nM [2]
JNJ-28583867 Drug Info Ki = 10.6 nM [9]
N-benzyl-4-cyclopentylpiperazine-1-carboxamide Drug Info Ki = 94 nM [8]
N-methyl-2-(pyridin-2-yl)ethanamine Drug Info Ki = 2030 nM [17]
Pitolisant Drug Info Ki = 0.16 nM [16]
ST-1025 Drug Info Ki = 11.2 nM [25]
ST-1093 Drug Info Ki = 20 nM [25]
UCL-2138 Drug Info Ki = 11 nM [15]
Verongamine Drug Info IC50 = 500 nM
VUF-5297 Drug Info Ki = 4.3 nM [3]
Action against Disease Model Cipralisant Drug Info GT-2331 demonstrated full agonism relative to (R)-alpha-methylhistamine in cAMP assays. In [35S]GTPgammaS binding assays, GT-2331 demonstrated partial agonism. Imetit showed full agonism in most assays, but it was slightly less efficacious in a neurotransmitter release assay and in [35S]GTPgammaS binding at the h uMan H3 receptor. To further examine these ligands, we coexpressed G alpha16 or chimeric G alpha q/i5 in h uMan embryonic kidney cells expressing the h uMan H3 receptor and assayed intracellular calci uM and cAMP levels. GT-2331 demonstrated full agonism in all assays of cAMP activity. However, in cells expressing G alpha16, they exhibited minimal agonism in calci uM mobilization assays, whereas imetit showed partial agonism. When G alpha q/i5 was used, the activity of both GT-2331 and proxyfan increased, whereas imetit became a full agonist [29]
References
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REF 5 Novel histamine H3 receptor antagonists based on the 4-[(1H-imidazol-4-yl)methyl]piperidine scaffold. Bioorg Med Chem Lett. 2006 Jan 15;16(2):395-9.
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REF 10 In vitro SAR of pyrrolidine-containing histamine H3 receptor antagonists: trends across multiple chemical series. Bioorg Med Chem Lett. 2008 Jan 1;18(1):355-9.
REF 11 Refinement of histamine H3 ligands pharmacophore model leads to a new class of potent and selective naphthalene inverse agonists. Bioorg Med Chem Lett. 2008 Aug 1;18(15):4377-9.
REF 12 The alkaloid conessine and analogues as potent histamine H3 receptor antagonists. J Med Chem. 2008 Sep 11;51(17):5423-30.
REF 13 Piperidine variations in search for non-imidazole histamine H(3) receptor ligands. Bioorg Med Chem. 2008 Sep 15;16(18):8729-36.
REF 14 2-Aryloxymethylmorpholine histamine H(3) antagonists. Bioorg Med Chem Lett. 2008 Nov 1;18(21):5796-9.
REF 15 Fluorinated non-imidazole histamine H3 receptor antagonists. Bioorg Med Chem Lett. 2009 Apr 15;19(8):2172-5.
REF 16 Diether derivatives of homo- or substituted piperidines as non-imidazole histamine H3 receptor ligands. Bioorg Med Chem. 2009 Apr 15;17(8):3037-42.
REF 17 5-hydroxyindole-2-carboxylic acid amides: novel histamine-3 receptor inverse agonists for the treatment of obesity. J Med Chem. 2009 Jul 9;52(13):3855-68.
REF 18 Design of a new histamine H3 receptor antagonist chemotype: (3aR,6aR)-5-alkyl-1-aryl-octahydropyrrolo[3,4-b]pyrroles, synthesis, and structure-acti... J Med Chem. 2009 Aug 13;52(15):4640-9.
REF 19 Synthesis and structure-activity relationships of 2-(1,4'-bipiperidin-1'-yl)thiazolopyridine as H3 receptor antagonists. Bioorg Med Chem Lett. 2009 Nov 1;19(21):6176-80.
REF 20 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 21 Role of hydrophobic substituents on the terminal nitrogen of histamine in receptor binding and agonist activity: development of an orally active hi... J Med Chem. 2010 May 13;53(9):3840-4.
REF 22 In vitro studies on a class of quinoline containing histamine H3 antagonists. Bioorg Med Chem Lett. 2010 Jun 1;20(11):3295-300.
REF 23 Discovery of N-{1-[3-(3-oxo-2,3-dihydrobenzo[1,4]oxazin-4-yl)propyl]piperidin-4-yl}-2-phenylacetamide (Lu AE51090): an allosteric muscarinic M1 rec... J Med Chem. 2010 Sep 9;53(17):6386-97.
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REF 25 Azole derivatives as histamine H3 receptor antagonists, part 2: C-C and C-S coupled heterocycles. Bioorg Med Chem Lett. 2010 Oct 1;20(19):5883-6.
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