Therapy Type: Small Molecule (timeline)
Target Type: Cholinergic System (timeline), Other Neurotransmitters (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Discontinued)
Company: GlaxoSmithKline (GSK)
GSK was developing this histamine H3 receptor antagonist for the treatment of Alzheimer's, schizophrenia, and multiple sclerosis. The rationale was to boost release in the brain of histamine, acetylcholine, noradrenaline, and dopamine in an attempt to enhance cognitive processes. In particular, histamine H3 receptor antagonism has been proposed to increase cholinergic signaling, which wanes with neurodegeneration in AD (Passani and Blandina, 1998; Bembenek et al., 2008; Bitner et al., 2011; Brioni et al., 2011). Blocking this receptor has been a target of several small-molecule therapeutic programs for cognition disorders at other companies as well, e.g. ABT-288, S38093.
Between 2007 and 2014, GSK conducted six clinical trials on this compound, three in Alzheimer's, two in multiple sclerosis, and one in schizophrenia.
Phase 1 studies assessed safety, pharmacokinetics, maximum tolerated dose, and brain distribution with the help of a PET imaging probe to this drug. A dose titration regimen emerging from some of these studies is published in the peer-reviewed literature (Nathan et al., 2013).
Also published are data from a Phase 2 study, in which 196 people with mild to moderate Alzheimer's disease were treated with GSK239512 or placebo for four months. The antagonist improved episodic memory but not other cognitive domains or clinical measures. It caused mild to moderate adverse events, predominantly headaches, dizziness, and problems sleeping (Grove et al., 2014). As of November 2015, this compound was no longer listed in GSK’s development pipeline.
For all clinical trials of GSK239512, see clinicaltrials.gov.
- Nathan PJ, Boardley R, Scott N, Berges A, Maruff P, Sivananthan T, Upton N, Lowy MT, Nestor PJ, Lai R. 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 Mar;10(3):240-51. PubMed.
- Grove RA, Harrington CM, Mahler A, Beresford I, Maruff P, Lowy MT, Nicholls AP, Boardley RL, Berges AC, Nathan PJ, Horrigan JP. 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 Jan;11(1):47-58. PubMed.
- Passani MB, Blandina P. Cognitive implications for H3 and 5-HT3 receptor modulation of cortical cholinergic function: a parallel story. Methods Find Exp Clin Pharmacol. 1998 Oct;20(8):725-33. PubMed.
- Bembenek SD, Keith JM, Letavic MA, Apodaca R, Barbier AJ, Dvorak L, Aluisio L, Miller KL, Lovenberg TW, Carruthers NI. Lead identification of acetylcholinesterase inhibitors-histamine H3 receptor antagonists from molecular modeling. Bioorg Med Chem. 2008 Mar 15;16(6):2968-73. Epub 2007 Dec 25 PubMed.
- Bitner RS, Markosyan S, Nikkel AL, Brioni JD. In-vivo histamine H3 receptor antagonism activates cellular signaling suggestive of symptomatic and disease modifying efficacy in Alzheimer's disease. Neuropharmacology. 2011 Feb-Mar;60(2-3):460-6. PubMed.
- Brioni JD, Esbenshade TA, Garrison TR, Bitner SR, Cowart MD. Discovery of histamine H3 antagonists for the treatment of cognitive disorders and Alzheimer's disease. J Pharmacol Exp Ther. 2011 Jan;336(1):38-46. PubMed.
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