GSK-189,254

GSK-189,254
Identifiers
	IUPAC name 6-[(3-cyclobutyl-1,2,4,5-tetrahydro-3-benzazepin-7-yl)oxy]-N-methylpyridine-3-carboxamide;
CAS Number	720690-73-3 ;
PubChem CID	9798547;
ChemSpider	7974313 ;
UNII	5T4TX6CO53;
ChEMBL	ChEMBL517140 ;
Chemical and physical data
Formula	C21H25N3O2
Molar mass	351.441 g/mol g·mol−1
3D model (JSmol)	Interactive image;
	SMILES c4cc1CCN(C3CCC3)CCc1cc4Oc(cc2)ncc2C(=O)NC;
	InChI InChI=1S/C21H25N3O2/c1-22-21(25)17-6-8-20(23-14-17)26-19-7-5-15-9-11-24(18-3-2-4-18)12-10-16(15)13-19/h5-8,13-14,18H,2-4,9-12H2,1H3,(H,22,25) ; Key:WROHEWWOCPRMIA-UHFFFAOYSA-N ;
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GSK-189,254 is a potent and selective H₃ histamine receptor inverse agonist developed by GlaxoSmithKline. It has subnanomolar affinity for the H₃ receptor (K_i = 0.2nM) and selectivity of over 10,000x for H₃ over other histamine receptor subtypes.^[1] Animal studies have shown it to possess not only stimulant and nootropic effects,^[2] but also analgesic action suggesting a role for H₃ receptors in pain processing in the spinal cord.^[3] GSK-189,254 and several other related drugs are currently being investigated as a treatment for Alzheimer's disease and other forms of dementia,^[4] as well as possible use in the treatment of conditions such as narcolepsy,^[5] or neuropathic pain which do not respond well to conventional analgesic drugs.^[6]

References

↑ "GSK189254, a novel H3 receptor antagonist that binds to histamine H3 receptors in Alzheimer's disease brain and improves cognitive performance in preclinical models". The Journal of Pharmacology and Experimental Therapeutics 321 (3): 1032–45. June 2007. doi:10.1124/jpet.107.120311. PMID 17327487.
↑ "Correlation between ex vivo receptor occupancy and wake-promoting activity of selective H3 receptor antagonists". The Journal of Pharmacology and Experimental Therapeutics 325 (3): 902–9. June 2008. doi:10.1124/jpet.107.135343. PMID 18305012.
↑ "Novel histamine H3 receptor antagonists GSK189254 and GSK334429 are efficacious in surgically-induced and virally-induced rat models of neuropathic pain". Pain 138 (1): 61–9. August 2008. doi:10.1016/j.pain.2007.11.006. PMID 18164820.
↑ "The histamine H3 receptor: an attractive target for the treatment of cognitive disorders". British Journal of Pharmacology 154 (6): 1166–81. July 2008. doi:10.1038/bjp.2008.147. PMID 18469850.
↑ "Differential effects of acute and repeat dosing with the H3 antagonist GSK189254 on the sleep-wake cycle and narcoleptic episodes in Ox-/- mice". British Journal of Pharmacology 157 (1): 104–17. May 2009. doi:10.1111/j.1476-5381.2009.00205.x. PMID 19413575.
↑ "Structurally novel histamine H3 receptor antagonists GSK207040 and GSK334429 improve scopolamine-induced memory impairment and capsaicin-induced secondary allodynia in rats". Biochemical Pharmacology 73 (8): 1182–94. April 2007. doi:10.1016/j.bcp.2007.01.007. PMID 17276409.

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[1] "GSK189254, a novel H3 receptor antagonist that binds to histamine H3 receptors in Alzheimer's disease brain and improves cognitive performance in preclinical models". The Journal of Pharmacology and Experimental Therapeutics 321 (3): 1032–45. June 2007. doi:10.1124/jpet.107.120311. PMID 17327487.

[2] "Correlation between ex vivo receptor occupancy and wake-promoting activity of selective H3 receptor antagonists". The Journal of Pharmacology and Experimental Therapeutics 325 (3): 902–9. June 2008. doi:10.1124/jpet.107.135343. PMID 18305012.

[3] "Novel histamine H3 receptor antagonists GSK189254 and GSK334429 are efficacious in surgically-induced and virally-induced rat models of neuropathic pain". Pain 138 (1): 61–9. August 2008. doi:10.1016/j.pain.2007.11.006. PMID 18164820.

[4] "The histamine H3 receptor: an attractive target for the treatment of cognitive disorders". British Journal of Pharmacology 154 (6): 1166–81. July 2008. doi:10.1038/bjp.2008.147. PMID 18469850.

[5] "Differential effects of acute and repeat dosing with the H3 antagonist GSK189254 on the sleep-wake cycle and narcoleptic episodes in Ox-/- mice". British Journal of Pharmacology 157 (1): 104–17. May 2009. doi:10.1111/j.1476-5381.2009.00205.x. PMID 19413575.

[6] "Structurally novel histamine H3 receptor antagonists GSK207040 and GSK334429 improve scopolamine-induced memory impairment and capsaicin-induced secondary allodynia in rats". Biochemical Pharmacology 73 (8): 1182–94. April 2007. doi:10.1016/j.bcp.2007.01.007. PMID 17276409.

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v t e Histamine receptor modulators
H₁	Agonists: 2-Pyridylethylamine Betahistine Histamine HTMT L-Histidine UR-AK49 Antagonists: First-generation: 4-Methyldiphenhydramine Alimemazine Antazoline Azatadine Bamipine Benzatropine (benztropine) Bepotastine Bromazine Brompheniramine Buclizine Captodiame Carbinoxamine Chlorcyclizine Chloropyramine Chlorothen Chlorphenamine Chlorphenoxamine Cinnarizine Clemastine Clobenzepam Clocinizine Cloperastine Cyclizine Cyproheptadine Dacemazine Decloxizine Deptropine Dexbrompheniramine Dexchlorpheniramine Dimenhydrinate Dimetindene Diphenhydramine Diphenylpyraline Doxylamine Embramine Etodroxizine Etybenzatropine (ethylbenztropine) Etymemazine Fenethazine Flunarizine Histapyrrodine Homochlorcyclizine Hydroxyethylpromethazine Hydroxyzine Isopromethazine Isothipendyl Meclozine Medrylamine Mepyramine (pyrilamine) Mequitazine Methafurylene Methapyrilene Methdilazine Moxastine Orphenadrine Oxatomide Oxomemazine Perlapine Phenindamine Pheniramine Phenyltoloxamine Pimethixene Piperoxan Pipoxizine Promethazine Propiomazine Pyrrobutamine Talastine Thenalidine Thenyldiamine Thiazinamium Thonzylamine Tolpropamine Tripelennamine Triprolidine Second/third-generation: Acrivastine Alinastine Astemizole Azelastine Bamirastine Barmastine Bepiastine Bepotastine Bilastine Cabastinen Carebastine Cetirizine Clemastine Clemizole Clobenztropine Desloratadine Dorastine Ebastine Efletirizine Emedastine Epinastine Fexofenadine Flezelastine Ketotifen Latrepirdine Levocabastine Levocetirizine Linetastine Loratadine Mapinastine Mebhydrolin Mizolastine Moxastine Noberastine Octastine Olopatadine Perastine Pibaxizine Piclopastine Quifenadine (phencarol) Rocastine Rupatadine Setastine Sequifenadine (bicarphen) Talastine Temelastine Terfenadine Vapitadine Zepastine Others: Atypical antipsychotics (e.g., aripiprazole, asenapine, Chemistry:Brexpiprazole
H₂	Agonists: Amthamine Betazole Dimaprit Histamine HTMT Impromidine L-Histidine UR-AK49 Antagonists: Bisfentidine Burimamide Cimetidine Dalcotidine Donetidine Ebrotidine Etintidine Famotidine Isolamtidine Lafutidine Lamtidine Lavoltidine (loxtidine) Lupitidine Metiamide Mifentidine Niperotidine Nizatidine Osutidine Oxmetidine Pibutidine Quisultazine (quisultidine) Ramixotidine Ranitidine Roxatidine Sufotidine Tiotidine Tuvatidine Venritidine Xaltidine Zolantidine
H₃	Agonists: α-Methylhistamine Cipralisant Histamine Imetit Immepip Immethridine L-Histidine Methimepip Proxyfan Antagonists: A-349,821 A-423,579 ABT-239 ABT-652 AZD5213 Bavisant Betahistine Burimamide Ciproxifan Clobenpropit Conessine Enerisant GSK-189,254 Impentamine Iodophenpropit Irdabisant JNJ-5207852 NNC 38-1049 PF-03654746 Pitolisant SCH-79687 Thioperamide VUF-5681
H₄	Agonists: 4-Methylhistamine α-Methylhistamine Histamine L-Histidine OUP-16 VUF-8430 Antagonists: JNJ-7777120 Mianserin Seliforant Thioperamide Toreforant VUF-6002
See also: Receptor/signaling modulators • Monoamine metabolism modulators • Monoamine reuptake inhibitors

Identifiers

IUPAC name 6-[(3-cyclobutyl-1,2,4,5-tetrahydro-3-benzazepin-7-yl)oxy]-N-methylpyridine-3-carboxamide
CAS Number	720690-73-3^N
PubChem CID	9798547
ChemSpider	7974313^N
UNII	5T4TX6CO53
ChEMBL	ChEMBL517140^N
Chemical and physical data
Formula	C₂₁H₂₅N₃O₂
Molar mass	351.441 g/mol g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES c4cc1CCN(C3CCC3)CCc1cc4Oc(cc2)ncc2C(=O)NC
InChI InChI=1S/C21H25N3O2/c1-22-21(25)17-6-8-20(23-14-17)26-19-7-5-15-9-11-24(18-3-2-4-18)12-10-16(15)13-19/h5-8,13-14,18H,2-4,9-12H2,1H3,(H,22,25)^N Key:WROHEWWOCPRMIA-UHFFFAOYSA-N^N
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GSK-189,254

Topic: Chemistry

References