Discovery of histamine H3 antagonists for the treatment of cognitive disorders and Alzheimer's disease.
H(3) antagonists increase the release of brain histamine, acetylcholine, noradrenaline, and dopamine, neurotransmitters that are known to modulate cognitive processes. The ability to release brain histamine supports the effect on attention and vigilance, but histamine also modulates other cognitive domains such as short-term and long-term memory. A number of H(3) antagonists, including 1-{3-[3-(4-chlorophenyl)propoxy]propyl}piperidine hydrochloride (BF2.649), (1R,3R)-N-ethyl-3-fluoro-3-[3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl]cyclobutane-1-carboxamide (PF-03654746), 6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride (GSK189254), MK-0249 (structure not yet disclosed), JNJ-17216498 (structure not yet disclosed), and ABT-288 (structure not yet disclosed), have advanced to the clinical area for the potential treatment of human cognitive disorders. H(3) antagonists exhibited wake-promoting effects in humans and efficacy in narcoleptic patients, indicating target engagement, but some of them were not efficacious in patients suffering from attention-deficit hyperactivity disorder and schizophrenic patients. Preclinical studies have also shown that H(3) antagonists activate intracellular signaling pathways that may improve cognitive efficacy and disease-modifying effects in Alzheimer's disease. Ongoing clinical studies will be able to determine the utility of H(3) antagonists for the treatment of cognitive disorders in humans.
Brioni
Jorge D
JD
Neuroscience Research (Dept. 4MN), Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA. jorge.brioni@abbott.com
Esbenshade
Tim A
TA
Garrison
Tiffany Runyan
TR
Bitner
Scott R
SR
Cowart
Marlon D
MD
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000523:psychology; D000818:Animals; D003072:Cognition Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000523:psychology; D055808:Drug Discovery / Q000639:trends; D054828:Histamine H3 Antagonists / Q000378:metabolism / Q000627:therapeutic use*; D006801:Humans; D018100:Receptors, Histamine H3 / Q000378:metabolism; D016896:Treatment Outcome
D054828:Histamine H3 Antagonists; D018100:Receptors, Histamine H3