The Histamine H3 Receptor as a Therapeutic Drug Target for Metabolic Disorders: Status, Challenges and Opportunities

Abstract

Since the histamine-3 receptor (H₃R) was cloned in 1999, huge efforts have been made by most of the key players in the pharmaceutical industry as well as in smaller biotech companies to increase the knowledge on this peculiar receptor, with the ultimate goal of bringing new drugs to the market. This review gives a survey on the most valuable chemical tools discovered so far and the significant pharmacological experiments on metabolic disease models published to date. Pharmacology of H₃R antagonists turns out to be very complex due to various functional activities, species selectivity, presence of H₃R isoforms and the poorly understood dichotomy in efficacy between CNS and metabolic disease models. Adding an extra layer of complexity, researchers have to cope with some recurrent safety concerns, some of them being tightly linked to the nature of the H₃R pharmacophore. Therefore this review also strives to summarize the major hurdles and some of the contradictions seen in the H₃R field, together with a brief overview of the clinical trials currently running.

Neuronal histamine and cognitive symptoms in Alzheimer's disease

“…It also inhibits high-voltage activated calcium channels, induces a G-protein dependent block of Ca2þ influx into axon terminals and thereby reduces the exocytosis of transmittercontaining vesicles (Celanire et al, 2005;Lazewska et al, 2014;Lin et al, 2011;Plancher, 2011).…”

Antihistamine Drugs

“…The results of their research are summarized in multiple reviews [59][60][61][62][63][64][65][66][67][68][69][70][71][72][73][74][75]. The results of their research are summarized in multiple reviews [59][60][61][62][63][64][65][66][67][68][69][70][71][72][73][74][75].…”

1‐[2‐(1‐Cyclobutylpiperidin‐4‐yloxy)‐6,7‐dihydro‐4H‐thiazolo[5,4‐c]pyridin‐5‐yl]propan‐1‐one: a Histamine H3 Receptor Inverse Agonist with Efficacy in Animal Models of Cognition

“…[12] Samelisant has completed Phase 1 clinical trial [13] and is currently being evaluated for safety, and efficacy in patients with narcolepsy with and without cataplexy. [14] Some of the literature reported discovery challenges that confounded the advancement of H 3 R antagonists and inverse agonists [15][16][17] included pharmacokinetic (PK) issues such as brain penetration and tissue distribution with long residence times and phospholipidosis issues. The progress of 4-{2-[2-((R)-2methylpyrrolidin-1-yl)ethyl]benzofuran-5-yl}benzonitrile (ABT-239), a H 3 R antagonist with interesting in vivo profile for cognitive enhancement [18] was halted for its hERG and cardiovascular liabilities.…”