Search for multifunctional agents against Alzheimer’s disease among non-imidazole histamine H3 receptor ligands. In vitro and in vivo pharmacological evaluation and computational studies of piperazine derivatives

Abstract Introduction Majority of pharmacological agents used in the treatment of narcolepsy have several limitations. Both nonclinical and clinical evidences suggest usefulness of the histamine H3 receptor (H3R) inverse agonists for the treatment of narcolepsy and addressing several of the current limitations. Methods Extensive nonclinical studies were carried out for SUVN-G3031 and other pharmacological agents that are currently being used for the treatment of narcolepsy. Nonclinical parameters like inter-species binding affinity, selectivity profile, in vivo and in vitro ADME features, nonclinical efficacy, neurochemistry and safety were compared. Results SUVN-G3031 has no inter-species variation in binding affinity at H3R with less than 50% inhibition at 1 µM against 70 other targets. Unlike pitolisant, SUVN-G3031 has no significant binding affinity at sigma 1 and 2 receptor. SUVN-G3031 has no inhibition and induction liability towards major CYP enzymes and transporters. Pitolisant is reported to be a CYP3A4, CYP2B6, and CYP1A2 inducer and a CYP2D6 and OCT1 inhibitor. SUVN-G3031 has robust wake promoting effects. SUVN-G3031 showed negligible affinity towards hERG channel with IC50 > 10 µM and had no effects on any ECG parameters in dog telemetry study. SUVN-G3031 did not show convulsion in rats up to the tested dose of 100 mg/kg, p.o. Most of the pharmacological agents used for the treatment of narcolepsy have abuse liability; SUVN-G3031 produced no change in the striatal and accumbal dopamine levels in rats suggesting no propensity to induce abuse liability. Unlike competing H3R inverse agonists, SUVN-G3031 has no effects on fertility and embryo-fetal development up to the highest tested doses. Conclusion Nonclinical studies demonstrate superiority of SUVN-G3031 over pharmacological agents currently used in the treatment of narcolepsy. SUVN-G3031 is being evaluated in a Phase 2 study as monotherapy for the treatment of narcolepsy with and without cataplexy (ClinicalTrials.gov Identifier: NCT04072380). Support None

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Histamine H3 Receptor Ligands in the Group of (Homo)piperazine Derivatives

Current Medicinal Chemistry ◽

10.2174/0929867325666171123203550 ◽

2018 ◽

Vol 25 (14) ◽

pp. 1609-1626 ◽

Cited By ~ 5

Author(s):

Katarzyna Szczepanska ◽

Kamil Kuder ◽

Katarzyna Kiec-Kononowicz

Keyword(s):

Wide Spectrum ◽

Rational Drug Design ◽

Receptor Ligands ◽

High Biological Activity ◽

Histamine H3 Receptor ◽

Therapeutic Implications ◽

Piperazine Derivatives ◽

H3 Receptor ◽

High Level ◽

Histamine H3

Since its discovery in 1983, followed by gene cloning in 1999, the histamine H3 receptor served as an outstanding target for drug discovery. The wide spectrum of possible therapeutic implications makes H3R's one of the most researched areas in the vast GPCR ligands field - started from imidazole containing ligands, through various successful imidazole replacements, with recent introduction of Wakix® to pharmaceutical market. One such replacement is piperazine moiety, a significant versatile scaffold in rational drug design for most of the GPCR ligands. Therefore, herein, we review ligands built on piperazine, as well as its seven membered analogue azepine, that target H3R’s and their potential therapeutical applications, in order to elucidate the current state of the art in this vast field. Due to a high level of structural divergence among compounds described herein, we decided to divide them into groups, where the key division element was the position of nitrogen basicity decreasing moieties in (homo)piperazine ring. Paying attention to a number of published structures and their overall high biological activity, one can realize that the (homo)piperazine scaffold bids a versatile template also for histamine H3 receptor ligands. With two possible substitution sites and therefore a number of possible structural combinations, piperazine derivatives stand as one of the largest group of high importance among H3R ligands.

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