Synthesis and Preliminary Pharmacological Investigation of New N‐Substituted‐N‐[ω‐(ω‐phenoxy‐alkylpiperazin‐1‐yl)alkyl]guanidines as Non‐Imidazole Histamine H₃ Antagonists

Abstract

Novel, potent non-imidazole histamine H(3) receptor antagonists were prepared. Detailed structure-activity studies revealed that N-(4-trifluoromethylbenzyl)-N-[4-(7-phenoxyheptylpiperazin-1-yl)butyl]guanidine (pA(2) = 8.49 ± 0.05), 1h, and N-(4-nitrobenzyl)-N-[4-(7-phenoxyheptylpiperazin-1-yl)butyl]guanidine (pA(2) = 8.43 ± 0.05), 1l, exhibit high affinity for the H(3) histamine receptor. The most potent antagonists in this series, 1e, 1h, and 1l, were also in vitro tested as H(1) receptor antagonists, showing weak H(1) -antagonistic activity with pA(2) = 6.70 ± 0.09, pA(2) = 6.46 ± 0.09, and pA(2) = 6.65 ± 0.11, respectively.

4-Hydroxypiperidines and Their Flexible 3-(Amino)propyloxy Analogues as Non-Imidazole Histamine H3 Receptor Antagonist: Further Structure–Activity Relationship Exploration and In Vitro and In Vivo Pharmacological Evaluation

“…Previously, our laboratory has described several non-imidazole piperazine- [ 28 , 29 ] and 4-hydroxypiperidine-based histamine H 3 antagonists with a moderate to pronounced affinity for the receptor [ 30 , 31 ]. The structure–activity relationship (SAR) of 4-hydroxypiperidines series showed that the most potent compounds, under in vitro screening conditions, were the benzofuranylpiperidinyloxy 1a ( ADS-003 ) (pA 2 = 8.47; Figure 1 ) [ 31 ] (for reference, thioperamide pA 2 = 8.67) and benzyl 1d (pA 2 = 7.79; Figure 1 ) derivatives [ 30 ].…”

Guanidine Derivatives: How Simple Structural Modification of Histamine H3R Antagonists Has Led to the Discovery of Potent Muscarinic M2R/M4R Antagonists

“…Compounds based on 1-[4-(piperazin-1-yl)but-1-yl]guanidine proved to be key to maintaining a high affinity at the histamine H 3 R. Based on previously obtained data of the guanidine series, two representative of the lead compounds, that is, ADS1017 and ADS1020 , were selected for further structural optimization. 31 , 32 In this paper, we have focused on the synthesis and pharmacological evaluation of a guanidine series where a flexible alkyl chain consisting of seven methylene groups, present in the lead compounds, is replaced by 1,4-cyclohexylene or p -phenylene group connected directly or by a methylene group to piperazine and phenoxy moieties. Additionally, for derivatives bearing a 1,4-disubstituted cyclohexylene group, the ( E ) and ( Z ) isomers were separated and pharmacologically tested independently ( Chart 2 ).…”

Design, synthesis, andin vitroandin vivocharacterization of 1-{4-[4-(substituted)piperazin-1-yl]butyl}guanidines and their piperidine analogues as histamine H3receptor antagonists

“…N-Benzyl-4-(4-(7-phenoxyheptyl)piperazin-1-yl)butan-1-amine was prepared according to Staszewski and Walczyński. 29…”

“…28 Previously, we have reported the synthesis and preliminary pharmacological in vitro characterization of a series of potent histamine H 3 receptor non-imidazole antagonists belonging to the class of 1-substituted-1-{ω-[4-(ω-phenoxyalkyl)piperazin-1-yl]alkyl}guanidines. 29 The prominent members of this family are compounds carrying electron-withdrawing substituents in position 1 of the guanidine moiety or a chlorine atom at position 4 in the benzene ring, 1a (ADS-1024; pA 2 = 8.43), 1b (ADS-1020; pA 2 = 8.49), 1d, (ADS-1022; pA 2 = 7.80), respectively, and an unsubstituted benzyl residue 1c (ADS-1017; pA 2 = 8.21) ((Chart 1) for reference thioperamide (pA 2 = 8.72)). These compounds were also routinely screened for potency towards the histamine H 1 receptor and were found to possess weak but competitive H 1 antagonistic activity (pA 2 = 6.65, pA 2 = 6.46, pA 2 = 6.62, and pA 2 = 6.70, respectively) for this site in the functional assay on isolated tissue preparations of the guinea-pig ileum.…”

“…Throughout the study, we choose to retain the length of the linkers connecting the phenoxy and guanidine residues with the piperazine and piperidine rings (the alkyl chain con-tains seven and four methylene groups, respectively), which is optimal according to our previous results. 29 In continuation of our search for new highly active and selective non-imidazole histamine H 3 receptor antagonists, the first part of this study aimed to clarify whether both nitrogen atoms in the piperazine ring, present in the parent compounds 1a and 1b, are necessary to maintain a high activity or whether only one of them (and which one) is absolutely necessary to retain the activity. Therefore, two piperidine analogues, 2a (ADS-1025) and 2b (ADS-1026) (Chart 1), of the lead compound 1b were synthesized and pharmacologically evaluated (functionally on the in vitro test system using guinea pig jejunum preparations).…”