Progress in the development of histamine H₃ receptor antagonists/inverse agonists: a patent review (2013-2017)

References

• Arrang JM , Garbarg M , Schwartz JC. Autoinhibtion of brain histamine release mediated by a novel class (H3) of histamine receptor. Nature. 1983;302:832–837.
   PubMed Web of Science ®Google Scholar
• Panula P , Chazot PL , Cowart M , et al. International Union of basic and clinical pharmacology. XCVIII. Histamine receptors. Pharmacol Rev. 2015;67:601–655.
   PubMed Web of Science ®Google Scholar
• Nieto-Alamilla G , Márquez-Gómez R , García-Gálvez A-M , et al. The histamine H3 receptor: structure, pharmacology and function. Mol Pharmacol. 2016;90:649–673.
   PubMed Web of Science ®Google Scholar
• Schlicker E , Kathmann M. Role of the histamine H3 receptor in the central nervous system. Handb Exp Pharmacol. 2017;241:277–299.
   PubMedGoogle Scholar
• Lovenberg TW , Roland BL , Wilson SJ , et al. Cloning and functional expression of the human histamine H3 receptor. Mol Pharmacol. 1999;55:1101–1107.
   PubMed Web of Science ®Google Scholar
• Hancock AA , Esbenshade TA , Krueger KM , et al. Genetic aspects to pharmacological heterogeneity of histamine H3 receptors. Life Sci. 2003;73:3043–3072.
   PubMed Web of Science ®Google Scholar
• Arrang JM , Morisset S , Gbahou F . Constitutive activity of the histamine H3 receptor. Trends Pharmacol Sci. 2007;28:350–357.
   PubMed Web of Science ®Google Scholar
• Berlin M , Boyce CW , De Lera Ruiz M . Histamine H3 receptor as a drug discovery target. J Med Chem. 2011;54:26–53.
   PubMed Web of Science ®Google Scholar
• Sadek B , Saad A , Sadeq A , et al. Histamine H3 receptor as a potential target for cognitive symptoms in neuropsychiatric diseases. Behav Brain Res. 2016;312:415–430.
   PubMed Web of Science ®Google Scholar
• Provensi G , Blandina P , Passani MB . The histaminergic system as a target for the prevention of obesity and metabolic syndrome. Neuropharmacology. 2016;106:3–12.
   PubMed Web of Science ®Google Scholar
• Bhowmik M , Khanam R , Vohora D . Histamine H3 receptor antagonists in relation to epilepsy and neurodegeneration: a systemic consideration of recent progress and perspectives. Br J Pharmacol. 2012;167:1398–1414.
   Web of Science ®Google Scholar
• Sadek B , Łażewska D , Hagenow S , et al. Histamine H3R antagonists: from scaffold hopping to clinical candidates. In: Blandina P , Passani MB , editors. Histamine receptors. Cham, Switzerland: Springer International Publishing; 2016. p. 109–156.
   Google Scholar
• Krementsov DN , Wall EH , Martin RA , et al. Histamine H3 receptor integrates peripheral inflammatory signals in the neurogenic control of immune responses and autoimmune disease susceptibility. PLoS One. 2013;8(7):e62743.
   PubMed Web of Science ®Google Scholar
• Rapanelli M , Pittenger C . Histamine and histamine receptors in Tourette syndrome and other neuropsychiatric conditions. Neuropharmacology. 2016;106:85–90.
   PubMed Web of Science ®Google Scholar
• Iida T , Yoshikawa T , Kárpáti A , et al. JNJ10181457, a histamine H3 receptor inverse agonist, regulates in vivo microglial functions and improves depression-like behaviours in mice. Biochem Biophys Res Commun. 2017;488:534–540.
   PubMed Web of Science ®Google Scholar
• Dudek M , Kuder K , Kołaczkowski M , et al. H3 histamine receptor antagonist pitolisant reverses some subchronic disturbances induced by olanzapine in mice. Metab Brain Dis. 2016;31:1023–1029.
   PubMed Web of Science ®Google Scholar
• Bahi A , Schwed JS , Walter M , et al. Anxiolytic and antidepressant-like activities of the novel and potent non-imidazole histamine H₃ receptor antagonist ST-1283. Drug Des Devel Ther. 2014;8:627–637.
   PubMed Web of Science ®Google Scholar
• Whittaker DS , Wang HB , Loh DH , et al. Possible use of a H3R antagonist for the management of nonmotor symptoms in the Q175 mouse model of Huntington’s disease. Pharmacol Res Perspect. 2017;5:e00344.
   Web of Science ®Google Scholar
• Baronio D , Castro K , Gonchoroski T , et al. Effects of an H3R antagonist on the animal model of autism induced by prenatal exposure to valproic acid. PLoS One. 2015;10:e0116363.
   PubMed Web of Science ®Google Scholar
• Arrang JM , Garbarg M , Lancelot JC , et al. Higly potent and selective ligands for histamine H3 receptors. Nature. 1987;327:117–123.
   PubMed Web of Science ®Google Scholar
• Ganellin CR , Leurquin F , Piripitsi A , et al. Synthesis of potent non-imidazole histamine H3 receptor antagonists. Arch Pharm Pharm Med Chem. 1998;331:395–404.
   PubMed Web of Science ®Google Scholar
• Sander K , Kottke T , Stark H . Histamine H3 receptor antagonists go to clinics. Biol Pharm Bull. 2008;31:2163–2181.
   PubMed Web of Science ®Google Scholar
• Tozer MJ , Kalindjian SB . Histamine H3 receptor antagonists. Exp Opin Ther Pat. 2000;10:1045–1055.
   Web of Science ®Google Scholar
• Stark H . Recent advances in histamine H3/H4 receptor ligands. Exp Opin Ther Pat. 2003;13:851–865.
   Web of Science ®Google Scholar
• Berlin M , Boyce CW . Recent advances in the development of histamine H3 antagonists. Exp Opin Ther Pat. 2007;17:675–687.
   PubMed Web of Science ®Google Scholar
• Łażewska D , Kieć-Kononowicz K . Recent advances in histamine H3 receptor antagonists/inverse agonists. Exp Opin Ther Pat. 2010;20:1147–1169.
   PubMed Web of Science ®Google Scholar
• Łażewska D , Kieć-Kononowicz K . New developments around histamine H3 receptor antagonists/inverse agonists: a patent review (2010 - present). Exp Opin Ther Pat. 2014;24:89–111.
   Google Scholar
• Khanfar MA , Affini A , Lutsenko K , et al. Multiple targeting approaches on histamine H3 receptor antagonists. Front Neurosci. 2016;10:201.
   Google Scholar
• Procopiou PA , Ancliff RA , Gore PM , et al. The discovery of quinolone based single-ligand human H1 and H3 receptor antagonists. Bioorg Med Chem Lett. 2016;26:5855–5859.
   PubMed Web of Science ®Google Scholar
• Darras FH , Pockes S , Huang G , et al. Synthesis, biological evaluation, and computational studies of Tri- and tetracyclic nitrogen-bridgehead compounds as potent dual-acting AChE inhibitors and hH3 receptor antagonists. ACS Chem Neurosci. 2014;5:225–242.
   PubMed Web of Science ®Google Scholar
• Khan N , Saad A , Nurulain SM , et al. The dual-acting H3 receptor antagonist and AChE inhibitor UW-MD-71 dose-dependently enhances memory retrieval and reverses dizocilpine-induced memory impairment in rats. Behav Brain Res. 2016;297:155–164.
   PubMed Web of Science ®Google Scholar
• Lepailleur A , Freret T , Lemaitre S , et al. Dual histamine H3R/serotonin 5-HT4R ligands with antiamnesic properties: pharmacophore-based virtual screening and polypharmacology. J Chem Inf Model. 2014;54:1773–1784.
   PubMed Web of Science ®Google Scholar
• Pala D , Scalvini L , Lodola A , et al. Synthesis and characterization of new bivalent agents as melatonin- and histamine H3 – ligands. Int J Mol Sci. 2014;15:16114–16133.
   PubMed Web of Science ®Google Scholar
• Schaller D , Hagenow S , Alpert G , et al. Systemic data mining reveals synergistic H3R/MCHR1 ligands. ACS Med Chem Lett. 2017;8:648–653.
   PubMed Web of Science ®Google Scholar
• Bautista-Aguilera O , Hagenow S , Palomino-Antolin A , et al. Multitarget-directed ligands combining cholinesterase and monoamine oxidase inhibition with histamine H3R antagonism for neurodegenerative diseases. Angew Chem Int Ed. 2017;56:12765-12769.
   Web of Science ®Google Scholar
• Sheng R , Tang L , Jiang L , et al. Novel 1-phenyl-3-hydroxy-4-pyridinone derivatives as multifunctional agents for the therapy of Alzheimer’s disease. ACS Chem Neurosci. 2016;7:69–81.
   PubMed Web of Science ®Google Scholar
• Bao X , Jin Y , Liu X , et al. Synthesis and biological evaluation of XB-1 analogues as novel histamine H3 receptor antagonists and neuroprotective agents. RSC Adv. 2014;4:6761–6775.
   Web of Science ®Google Scholar
• Sadek B , Schwed JS , Subramanian D , et al. Non-imidazole histamine H3 receptor ligands incorporating antiepileptic moiety. Eur J Med Chem. 2014;77:269–279.
   PubMed Web of Science ®Google Scholar
• Gunn RN , Rabiner EA . Imaging in central nervous system drug discovery. Semin Nucl Med. 2017;47:89–98.
   PubMed Web of Science ®Google Scholar
• Yanai K , Ryu JH , Watanabe T , et al. Labeling of histamine H1, H2, and H3 receptor antagonists with carbon-11 using on-line methylation system: potential radiopharmaceuticals for PET studies. J Labelled Comp Radiopharm. 1994;35:520.
   Google Scholar
• Funke U , Vugts DJ , Janssen B , et al. 11C-labeled and 18F-labeled PET ligands for subtype-specific imaging of histamine receptors in the brain. J Labelled Comp Radiopharm. 2013;56:120–129.
   PubMed Web of Science ®Google Scholar
• Airaksinen AJ , Jablonowski JA , van der Mey M , et al. Radiosynthesis and biodistribution of a histamine H3 receptor antagonist 4-[3-(4-piperidin-1-yl-but-1-ynyl)-[11C]benzyl]-morpholine: evaluation of a potential PET ligand. Nucl Med Biol. 2006;33:801–810.
   PubMed Web of Science ®Google Scholar
• Ashworth S , Rabiner EA , Gunn RN , et al. Evaluation of 11C-GSK189254 as a novel radioligand for the H3 receptor in humans using PET. J Nucl Med. 2010;51:1021–1029.
   PubMed Web of Science ®Google Scholar
• Logan J , Carruthers NI , Letavic MA , et al. Blockade of the brain histamine H3 receptor by JNJ-39220675: preclinical PET studies with [11C]GSK189254 in anesthetized baboon. Psychopharmacology (Berl). 2012;223:447–455.
   PubMed Web of Science ®Google Scholar
• Jucaite A , Takano A , Bostrom E , et al. AZD5213: a novel histamine H3 receptor antagonist permitting high daytime and low nocturnal H3 receptor occupancy, a PET study in human subjects. Int J Neuropsychopharmacol. 2013;16:1231–1239.
   PubMed Web of Science ®Google Scholar
• Ashworth S , Berges A , Rabiner EA , et al. Unexpectedly high affinity of a novel histamine H(3) receptor antagonist, GSK239512, in vivo in human brain, determined using PET. Br J Pharmacol. 2014;171:1241–1249.
   PubMed Web of Science ®Google Scholar
• Gallezot JD , Planeta B , Nabulsi N , et al. Determination of receptor occupancy in the presence of mass dose: [11C]GSK189254 PET imaging of histamine H3 receptor occupancy by PF-03654746. J Cereb Blood Flow Metab. 2017;37:1095–1107.
   PubMed Web of Science ®Google Scholar
• Koga K , Maeda J , Tokunaga M , et al. Development of TASP0410457 (TASP457), a novel dihydroquinolinone derivative as a PET radioligand for central histamine H3 receptors. EJNMMI Res. 2016;6:11.
   PubMed Web of Science ®Google Scholar
• Hanyu M , Kawamura K , Takei M , et al. Radiosynthesis and quality control of [11C]TASP457 as a clinically useful PET ligand for imaging of histamine H3 receptors in human brain. Nucl Med Biol. 2016;43:679–684.
   PubMed Web of Science ®Google Scholar
• Shou M , Varnäs K , Jureus A , et al. Discovery and preclinical validation of [11C]AZ13153556, a novel probe for the histamine type 3 receptor. ACS Chem Neurosci. 2016;7:177–184.
   PubMed Web of Science ®Google Scholar
• Lewis DY , Champion S , Wyper D , et al. Assessment of [125I]WYE-230949 as a novel histamine H3 receptor radiopharmaceutical. PLoS One. 2014;9:e115876.
   PubMed Web of Science ®Google Scholar
• Hesk D , Borges S , Dumpit R , et al. Synthesis of 3H, 13C, 2H3, 15N and 14C-labelled SCH 466036, a histamine 3 receptor antagonist. J Labelled Comp Radiopharm. 2015;58:36–41.
   PubMed Web of Science ®Google Scholar
• Siméon FG , Culligan WJ , Lu S , et al. 11C-labeling of aryl ketones as candidate histamine subtype-3 receptor PET radioligands through Pd(0)-mediated 11C-carbonylative coupling. Molecules. 2017;22:e792.
   PubMed Web of Science ®Google Scholar
• Kimura Y , Seki C , Ikoma Y , et al. [11C]TASP457, a novel PET ligand for histamine H3 receptors in human brain. Eur J Nucl Med Mol Imaging. 2016;43:1653–1663.
   PubMed Web of Science ®Google Scholar
• Van Leare KJ , Sanabria-Bohórquez SM , Mozley DP , et al. 11C-MK-8278 PET as a tool for pharmacodynamic brain occupancy of histamine 3 receptor inverse agonists. J Nucl Med. 2014;55:65–72.
   PubMed Web of Science ®Google Scholar
• Franco R , Martinez-Pinilla E , Lanciego JL , et al. Basic pharmacological and structural evidence for class A G-protein-coupled receptor heteromerization. Front Pharmacol. 2016;7:76.
   PubMed Web of Science ®Google Scholar
• Hiller C , Kühhorn J , Gmeiner P . Class A G-protein-coupled receptor (GPCR) dimers and bivalent ligands. J Med Chem. 2013;56:6542–6559.
   PubMed Web of Science ®Google Scholar
• Ferrada C , Moreno E , Casadó V , et al. Marked changes in signal transduction upon heteromerization of dopamine D1 and histamine H3 receptors. Br J Pharmacol. 2009;157:64–75.
   PubMed Web of Science ®Google Scholar
• Ferrada C , Ferré S , Casadó V , et al. Interactions between histamine H3 and dopamine D2 receptors and the implications for striatal function. Neuropharmacology. 2008;55:190–197.
   PubMed Web of Science ®Google Scholar
• Moreno E , Hoffmann H , Gonzalez-Sepúlveda M , et al. Dopamine D1-histamine H3 receptor heteromers provide a selective link to MAPK signaling in GABAergic neurons of the direct striatal pathway. J Biol Chem. 2011;286:5846–5854.
   PubMed Web of Science ®Google Scholar
• Ellenbroek BA , Ghiabi B . The other side of the histamine H3 receptor. Trends Neurosci. 2014;37:191–199.
   PubMed Web of Science ®Google Scholar
• Marquez-Gomez R , Gutierrez-Rodelo C , Robins MT , et al. On the existence of a histamine H3-adenosine A2A receptor heteromer. 45th Annual Meeting of the EHRS, Florence; 2016 May 11-14; Italy; abstract book p. 48
   Google Scholar
• Morales-Figueroa G-E , Gonzalez-Pantoja R , Escamilla-Sanchez J , et al. Functional interactions between histamine H3 and adenosine A2A receptors in rat striato-pallidal nerve terminals. 46th Annual Meeting of the EHRS, Amsterdam; 2017 May 11-13; the Netherlands; abstract book p. 84.
   Google Scholar
• Rodríguez-Ruiz M , Moreno E , Moreno-Delgado D , et al. Heteroreceptor complexes formed by dopamine D1, histamine H3, and N-methyl-D-aspartate glutamate receptors as targets to prevent neuronal death in Alzheimer’s disease. Mol Neurobiol. 2017;54:4537–4550.
   PubMed Web of Science ®Google Scholar
• Grove RA , Harrington CM , Mahler A , et al. A randomized, double-blind, placebo-controlled, 16-week study of the H3 receptor antagonist, GSK239512 as a monotherapy in subjects with mild-to-moderate Alzheimer’s disease. Curr Alzheimer Res. 2014;11:47–58.
   PubMed Web of Science ®Google Scholar
• Egan M , Yaari R , Liu L , et al. Pilot randomized controlled study of a histamine receptor inverse agonist in the symptomatic treatment of AD. Curr Alzheimer Res. 2012;9:481–490.
   PubMed Web of Science ®Google Scholar
• Haig GM , Pritchett Y , Meier A , et al. A randomized study of H3 antagonist ABT-288 in mild-to-moderate Alzheimer’s dementia. J Alzheimer’s Disease. 2014;42:959–971.
   PubMed Web of Science ®Google Scholar
• SANOFI SA . An H3 receptor antagonist combined with a cholinesterase inhibitor for use in the treatment of Alzheimer’s disease. WO2015032966. 2015.
   Google Scholar
• Stemmelin J , Kirkesseli S , Martincova R , et al. A phase 2 study to investigate the effects of SAR110894 on cognition, daily function, apathy and sleep in mild to moderate Alzheimer’s disease patients. J Nutr Health Aging. 2013;17:804-805.
   Google Scholar
• Weisler RH , Pandina GJ , Daly EJ , et al. Randomized clinical study of a histamine H3 receptor antagonist for the treatment of adults with attention-deficit hyperactivity disorder. CNS Drugs. 2012;26:421–434.
   PubMed Web of Science ®Google Scholar
• Herring WJ , Wilens TE , Adler LA , et al. Randomized controlled study of the histamine H3 inverse agonist MK-0249 in adult attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2012;73:e891- e898.
   PubMedGoogle Scholar
• Haig GM , Bain E , Robieson W , et al. A randomized trial of the efficacy and safety of the H3 antagonist ABT-288 in cognitive impairment associated with schizophrenia. Schizophr Bull. 2014;40:1433–1442.
   PubMed Web of Science ®Google Scholar
• Jarskog LF , Lowy MT , Grove RA , et al. A Phase II study of a histamine H₃ receptor antagonist GSK239512 for cognitive impairment in stable schizophrenia subjects on antipsychotic therapy. Schizophr Res. 2015;164:136–142.
   PubMed Web of Science ®Google Scholar
• Egan MF , Zhao X , Gottwald R , et al. Randomized crossover study of the histamine H3 inverse agonist MK-0249 for the treatment of cognitive impairment in patients with schizophrenia. Schizophr Res. 2013;146:224–230.
   PubMed Web of Science ®Google Scholar
• Stokes JR , Romero FA Jr , Allan RJ , et al. The effects of an H3 receptor antagonist (PF-03654746) with fexofenadine on reducing allergic rhinitis symptoms. J Allergy Clin Immunol. 2012;129:409–412.
   Google Scholar
• North ML , Walker TJ , Steacy LM , et al. Add-on histamine receptor-3 antagonist for allergic rhinitis: a double blind randomized crossover trial using the environmental exposure unit. Allergy Asthma Clin Imunnol. 2014;10:33.
   PubMed Web of Science ®Google Scholar
• Delay-Yates P , Ambery C , Sweeney L , et al. The efficacy and tolerability of two novel H1/H3 receptor antagonists in seasonal allergic rhinitis. Int Arch Allergy Immunol. 2012;158:84–98.
   PubMed Web of Science ®Google Scholar
• Barchuk WT , Salapatek AM , Ge T , et al. A proof-of-concept study of the effect of a novel H3-receptor antagonist in allergen-induced nasal congestion. J Allergy Clin Immunol. 2013;132:838–846.
   PubMed Web of Science ®Google Scholar
• Schwartzbach CJ , Grove RA , Brown R , et al. Lesion remyelinating activity of GSK239512 versus placebo in patients with relapsing-remitting multiple sclerosis: a randomised, single-blind, phase II study. J Neurol. 2017;264:304–315.
   PubMed Web of Science ®Google Scholar
• Leu-Semenescu S , Nittur N , Golmard JL , et al. Effects of pitolisant, a histamine H3 inverse agonist, in drug-resistant idiopathic and symptomatic hypersomnia: a chart review. Sleep Med. 2014;15:681–687.
   PubMed Web of Science ®Google Scholar
• Lin J-S , Dauvilliers Y , Arnulf I , et al. An inverse agonist of the histamine H(3) receptor improves wakefulness in narcolepsy: studies in orexin-/- mice and patients. Neurobiol Dis. 2008;30:74–83.
   PubMed Web of Science ®Google Scholar
• Dauvillers Y , Bassetti C , Lammers GJ , et al. Pitolisant versus placebo or modafinil in patients with narcolepsy: a double-blind, randomised trial. Lancet Neurol. 2013;12:1068–1075.
   PubMed Web of Science ®Google Scholar
• Szakacs Z , Dauvilliers Y , Mikhaylov V , et al. Safety and efficacy of pitolisant on cataplexy in patients with narcolepsy: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2017;16:200–207.
   PubMed Web of Science ®Google Scholar
• Inocente C , Arnulf I , Bastuji H et al. Pitolisant, an inverse agonist of the histamine H3 receptor: an alternative stimulant for narcolepsy-cataplexy in teenagers with refractory sleepiness. Clin Neuropharmacol. 2012;35:55–60.
   PubMed Web of Science ®Google Scholar
• Sun H , MacLeod C , Mostoller K , et al. Early-stage comparative effectiveness: randomized controlled trial with histamine inverse agonist MK-7288 in excessive daytime sleepiness patients. J Clin Pharmacol. 2013;53:1294–1302.
   PubMed Web of Science ®Google Scholar
• Herring WJ , Liu K , Hutzelmann J , et al. Alertness and psychomotor performance effects of the histamine-3 inverse agonist MK-0249 in obstructive sleep apnea patients on continuous positive airway pressure therapy with excessive daytime sleepiness: a randomized adaptive crossover study. Sleep Med. 2013;10:955–963.
   Google Scholar
• Collart Dutilleul P , Ryvlin P , Kahane P , et al. Exploratory phase II trial to evaluate the safety and the antiepileptic effect of pitolisant (BF2.649) in refractory partial seizures, given as adjunctive treatment during 3 months. Clin Neuropharmacol. 2016;39:188–193.
   PubMed Web of Science ®Google Scholar
• Kasteleijn-Nolst Trenite D , Parain D , Genton P , et al. Efficacy of the histamine 3 receptor (H3R) antagonist pitolisant (formerly known as tiprolisant; BF2.649) in epilepsy: dose-dependent effects in the human photosensitivity model. Epilepsy Beh. 2013;28:66–70.
   PubMed Web of Science ®Google Scholar
• Zoethout RWM , Iannone R , Bloem BR , et al. The effects of a novel histamine-3 receptor inverse agonist on essential tremor in comparison to stable levels of alcohol. J Psychopharmacol. 2012;26:292–302.
   PubMed Web of Science ®Google Scholar
• Valko PO , Gavrilov YV , Yamamoto M , et al. Increase of histaminergic tuberomammillary neurons in narcolepsy. Ann Neurol. 2013;74:794–804.
   PubMed Web of Science ®Google Scholar
• John J , Thannickal TC , McGregor R , et al. Greatly increased numbers of histamine cells in human narcolepsy with cataplexy. Ann Neurol. 2013;74:786–793.
   PubMed Web of Science ®Google Scholar
• [cited 2017 Nov 15]. Available from:  http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2015/11/WC500196774.pdf
   Google Scholar
• Kollb-Sielecka M , Demolis P , Emmerich J , et al. The European Medicines Agency review of pitolisant for treatment of narcolepsy: summary of the scientific assessment by the Committee for medicinal products for human use. Sleep Med. 2017;33:125–129.
   PubMed Web of Science ®Google Scholar
• Efficacy and safety study of BF2.649 in the treatment of excessive daytime sleepiness in narcolepsy (Harmony I) (COMPLETED). NCT01067222. [cited 2017 Nov 15 ]. Available from: www.ClinicalTrials.gov
   Google Scholar
• Effects of BF2.649 in the treatment of excessive daytime sleepiness in narcolepsy. (COMPLETED). NCT01638403. 2012 Jul 9. [cited 2017 Nov 15]. Available from: www.ClinicalTrials.gov
   Google Scholar
• Syed YY . Pitolisant: first global approval. Drugs. 2016;76:1313–1318.
   PubMed Web of Science ®Google Scholar
• Calik MW . Update on the treatment of narcolepsy: clinical efficacy of pitolisant. Nat Sci Sleep. 2017;9:127–133.
   PubMed Web of Science ®Google Scholar
• AAPA B.V . Multiple D2 a(nta)gonists/H3 antagonists for treatment of CNS-related disorders. WO2015069110. 2015.
   Google Scholar
• ABBVIE INC . Mercaptoamidine derivatives and methods of use. US20130040940. 2013.
   Google Scholar
• ACTIVE CONCEPTS LLC . H3 antagonist by-product, its manufacture and method of using by-product to reduce pigmentation in skin. WO201514817. 2015.
   Google Scholar
• ARENA PHARM INC . Modulators of the histamine H3 receptor and the treatment of disorders related thereto. WO2014028322. 2014.
   Google Scholar
• ARENA PHARM INC . Biphenyl-ethyl-pyrrolidine derivatives as histamine H3 receptor modulators for the treatment of cognitive disorders. WO2014110103. 2014.
   Google Scholar
• CEPHALON INC . Solid state forms of 6-[4-[3-(R)-2-methylpyrrolidine-1-yl)-propoxy]phenyl]2H-pyridazine-3-one hydrochloride. WO2014159776. 2014.
   Google Scholar
• RICHTER GEDEON NYRT . Histamine H3 antagonist steroidal carboxamides. WO2013027073. 2013.
   Google Scholar
• RICHTER GEDEON NYRT . H3 antagonists containing phenoxypiperidine core structure. WO2014136075. 2014.
   Google Scholar
• GLAXOSMITHKLINE . Therapeutic uses. WO2013107336. 2013.
   Google Scholar
• NOVARTIS AG . Carbamate/urea derivatives containing piperidin and piperazin rings as H3 receptor inhibitors. WO2013050987. 2013.
   Google Scholar
• NOVARTIS AG . Carbamate/urea derivatives. WO201413469. 2014.
   Google Scholar
• MEDISYNERGICS LLC . Histamine H3 receptor antagonists. US20160237052. 2016.
   Google Scholar
• OXYGEN HEALTHCARE RES PVT LTD . Benzothiazine compounds as H3 receptor ligands. WO2013076590. 2013.
   Google Scholar
• SANOFI SA . An H3 receptor antagonist for use in the treatment of Alzheimer’s disease. WO2013150150. 2013.
   Google Scholar
• SERVIER LAB . Novel association between 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide and an NMDA receptor antagonist and the pharmaceutical compositions which contain said association. WO2013083887. 2013.
   Google Scholar
• SERVIER LAB . Use of 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide for treating neuropathic pain. WO2014147353. 2014.
   Google Scholar
• SUVEN LIFE SCIENCES LTD . Acrylamide compounds as histamine H3 receptor ligands. WO2014030170. 2014.
   Google Scholar
• SUVEN LIFE SCIENCES LTD . Process for large scale production of N-[4-(1- cyclobutyl piperidin-4-yloxy) phenyl]-2-(morpholin-4-yl) acetamide dihydrochloride. WO2016027275. 2016.
   Google Scholar
• TAKEDA PHARMACEUTICAL . Compounds and their use to treat histamine H3 related disorders. WO2013027001. 2013.
   Google Scholar
• SUVEN LIFE SCIENCES LTD . Novel compounds as histamine H3 receptor ligands. WO2012114348. 2012.
   Google Scholar
• Babu MR , Muddana N , Mekala VR , et al. SUVN-G3031: a novel and potent histamine H3 receptor antagonist for potential treatment of cognitive deficits. Alzheimer’s & Dementia. 2014;10(Supplement):P459–P460.
   Google Scholar
• Benade VS , Daripelli S , Thentu JB , et al. SUVN-G3031, an H3 receptor inverse agonist, produces procognitive effects without affecting sleep in preclinical models. Alzheimer’s & Dementia. 2015;11(Supplement):P475.
   PubMedGoogle Scholar
• Bhyrapuneni G , Mudigonda K , Penta KK , et al. SUVN G3031, a potent and selective H3 receptor inverse agonist: safety, tolerability and pharmacokinetics in humans. Alzheimer’s & Dementia. 2016;12(Supplement):P618–P619.
   Google Scholar
• Muddana NR , Bhyrapuneni G , Mudigonda K , et al. SUVN-G3031, a selective H3 receptor inverse agonist: assessment of safety, tolerability and pharmacokinetics in healthy human volunteers. Alzeheimer’s & Dementia. 2017;13(Supplement):P261–P262.
   Google Scholar
• A study to investigate the safety, tolerability and pharmacokinetics of SUVN-G3031 in healthy subjects. (COMPLETED). NCT02342041. [cited 2017 Nov 15 ]. Available from: www.ClinicalTrials.gov
   Google Scholar
• A study to investigate the effect of food, gender, and age on the pharmacokinetic profile of SUVN-G3031 in healthy subjects (COMPLETED). NCT02881294. [cited 2017 Nov 15 ]. Available from: www.ClinicalTrials.gov
   Google Scholar
• CEPHALON INC . Pyridazinone derivatives.WO2008013838. 2008.
   Google Scholar
• Hudkins RL , Raddatz R , Tao M , et al. Discovery and characterization of 6-{4-[3-(R)-2-methylpyrrolidin-1-yl)propoxy]phenyl}-2H-pyridazin-3-one (CEP-26401, irdabisant): a potent, selective histamine H3 receptor inverse agonist. J Med Chem. 2011;54:4781–4792.
   PubMed Web of Science ®Google Scholar
• Raddatz R , Hudkins RL , Mathiasen JR , et al. CEP-26401 (irdabisant), a potent and selective histamine H₃ receptor antagonist/inverse agonist with cognition-enhancing and wake-promoting activities. J Pharmacol Exp Ther. 2012;340:124–133.
   PubMed Web of Science ®Google Scholar
• Pharmacokinetics and Pharmacodynamics (PK/PD) of CEP-26401 in healthy subjects. (COMPLETED). NCT01903824. [cited 2017 Nov 15 ]. Available from: www.ClinicalTrials.gov
   Google Scholar
• Spiegelstein O , Stevens J , Van Gerven J , et al. Pharmacokinetics, pharmacodynamics and safety of CEP-26401, a high-affinity histamine-3 receptor antagonist, following single and multiple dosing in healthy subjects. J Psychopharmacol. 2016;30:983–993.
   PubMed Web of Science ®Google Scholar
• SANOFI AVENTIS . Tetrahydroisoquinoline sulfonamide derivatives, the preparation thereof, and the use of the same in therapeutics. WO2005118547. 2005.
   Google Scholar
• SANOFI AVENTIS . Novel fumarate salts of a histamine H3 receptor antagonist. WO2010151611. 2010.
   Google Scholar
• Griebel G , Pichat P , Pruniaux MP , et al. SAR110894, a potent histamine H₃-receptor antagonist, displays procognitive effects in rodents. Pharmacol Biochem Behav. 2012;102:203–214.
   PubMed Web of Science ®Google Scholar
• Griebel G , Decobert M , Jacquet A , et al. Awakening properties of newly discovered highly selective H₃ receptor antagonists in rats. Behav Brain Res. 2012;232:416–420.
   PubMed Web of Science ®Google Scholar
• Delay-Goyet P , Blanchard V , Schussler N , et al. SAR110894, a potent histamine H3-receptor antagonist, displays disease-modifying activity in a transgenic mouse model of tauopathy. Alzheimer’s & Dementia. 2016;2:267–280.
   Google Scholar
• Schindowski K , Bretteville A , Leroy K , et al. Alzheimer’s disease-like tau neuropathology leads to memory deficits and loss of functional synapses in a novel mutated tau transgenic mouse without any motor deficits. Am J Pathol. 2006;169:599–616.
   PubMed Web of Science ®Google Scholar
• Effect of different doses of SAR110894 on cognition in patients with mild to moderate Alzheimer’s disease on donepezil. (COMPLETED). NCT01266525. [cited 2017 Nov 15 ]. Available from: www.ClinicalTrials.gov
   Google Scholar
• SERVIER LAB . Novel azabicyclic derivatives, preparation method thereof and pharmaceutical compositions containing same. WO2005089747. 2005.
   Google Scholar
• SERVIER LAB . Process for synthesis and crystalline form of 4 hydrochloride -{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide, in addition to the associated free base and the pharmaceutical compositions containing same. WO2012168657. 2012.
   Google Scholar
• SERVIER LAB . Novel combination of 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide and an acetylcholinesterase inhibitor, and pharmaceutical compositions containing same. WO2012150412. 2012.
   Google Scholar
• Sors A , Panayi F , Bert L , et al. Mechanistic characterization of S38093, a novel inverse agonist at histamine H3 receptors. Eur J Pharmacol. 2017;803:11–23.
   PubMed Web of Science ®Google Scholar
• Panayi F , Sors A , Bert L , et al. In vivo pharmacological profile of S38093, a novel histamine H3 receptor inverse agonist. Eur J Pharmacol. 2017;803:1–10.
   PubMed Web of Science ®Google Scholar
• Guilloux JP , Samuels BA , Mendez-David I , et al. S38093, a histamine H3 antagonist/inverse agonist, promotes hippocampal neurogenesis and improves context discrimination task in aged mice. Sci Rep. 2017;7:42946.
   PubMed Web of Science ®Google Scholar
• Sors A , Krazem A , Kehr J , et al. The synergistic enhancing-memory effect of donepezil and S38093 (a Histamine H3 Antagonist) is mediated by increased neural activity in the septo-hippocampal circuitry in middle-aged mice. Front Pharmacol. 2016;7:492.
   PubMed Web of Science ®Google Scholar
• Chaumette T , Chapuy E , Berrocoso E , et al. Effects of S38093, an antagonist/inverse agonist of histamine H3 receptors, in models of neuropathic pain in rats. Eur J Pain. 2018;22:127-141.
   PubMed Web of Science ®Google Scholar
• Wang R , Chen Y , Guo T , et al. Histamine H3 receptor negatively regulates oligodendrocyte differentiation and myelination. Mult Scler. 2014;20(S1):341.
   Google Scholar
• GLAXO GROUP LTD . Benzodiazepine derivatives for the treatment of neurological disorders. WO2004056369. 2004.
   Google Scholar
• GLAXO GROUP LTD . Substituted piperidines as histamine H3 receptor ligands. WO200514571. 2005.
   Google Scholar
• Wilson DM , Apps J , Bailey N , et al. Identification of clinical candidates from the benzazepine class of histamine H3 recep-tor antagonists. Bioorg Med Chem Lett. 2013;23:6890–6896.
   PubMed Web of Science ®Google Scholar
• Bridging study with GSK239512 in patients with mild to moderate Alzheimer’s disease. (COMPLETED). NCT00675090. [cited 2017 Nov 15 ]. Available from: www.ClinicalTrials.gov
   Google Scholar
• Study to assess whether GSK239512 can remyelinate lesions in subjects with relapsing remitting multiple sclerosis. (COMPLETED). NCT01772199. 2013 Jan 17. [cited 2017 Nov 15]. Available from: www.ClinicalTrials.gov
   Google Scholar
• Study to evaluate the efficacy and safety of GSK239512 in Schizophrenia. (COMPLETED). NCT01009060. 2009 Nov 5. [cited 2017 Nov 15]. Available from: www.ClinicalTrials.gov
   Google Scholar
• GSK239512 DDI Study. (COMPLETED). NCT01802931. 2013 Jan 4. [cited 2017 Nov 15]. Available from: www.ClinicalTrials.gov
   Google Scholar
• An imaging study to investigate the distribution of GSK239512 in the brain. (COMPLETED). NCT00474513. 2007 May 15. [cited 2017 Nov 15]. Available from: www.ClinicalTrials.gov
   Google Scholar
• Study to evaluate the efficacy and safety of GSK239512 in Alzheimer’s disease. (COMPLETED). NCT01009255. 2009 Nov 5. [cited 2017 Nov 15]. Available from: www.ClinicalTrials.gov
   Google Scholar
• Nathan PJ , Boardley R , Scott N , et al. The safety, tolerability, pharmacokinetics and cognitive effects of GSK239512, a selective histamine H₃ receptor antagonist in patients with mild to moderate Alzheimer’s disease: a preliminary investigation. Curr Alzheimer Res. 2013;10:240–251.
   PubMed Web of Science ®Google Scholar
• Yoshida M , Takahashi Y , Inoue S . Histamine induces melanogenesis and morphologic changes by protein kinase A activation via H2 receptors in human normal melanocytes. J Invest Dermatol. 2000;114:334–342.
   PubMed Web of Science ®Google Scholar
• Ledneczki I , Tapolcsányi P , Gábor E , et al. Discovery of novel steroidal histamine H3 receptor antagonists/inverse agonists. Bioorg Med Chem Lett. 2017;27:4525–4530.
   PubMed Web of Science ®Google Scholar
• Ajani OO . Functionalized 1,4-benzothiazine: a versatile scaffold with diverse biological properties. Arch Pharm (Weinheim). 2012;345:841–851.
   PubMed Web of Science ®Google Scholar
• Anderson J , Stuhr-Hansem N , Zachariassen L , et al. Molecular determinants for selective recognition of antidepressants in the human serotonin and norepinephrine transporters. PNAS. 2011;108:12137-12142.
   Google Scholar
• Wingen K , Stark H . Scaffold variations in amine warhead of histamine H₃ receptor antagonists. Drug Discov Today Technol. 2013;10:e484–e489.
   Google Scholar