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

Abstract

The prominent members of 1-{4-[4-(substituted)piperazin-1-yl]butyl}guanidines as histamine H3 receptor antagonists.

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

“…This observation is consistent with the results of previous experiments. 31 We found that the activity differences in the studied group of compounds are related to ligand alignment in the hydrophobic regions between TM2, TM3, and TM7. This area includes a number of aromatic amino acids such as Y91 2.61 , Y94 2.64 , W110 3.28 , F398 7.39 , and W402 7.43 .…”

“…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 ).…”

“…Our previous study clarified whether both nitrogen atoms of the piperazine ring are necessary to maintain a high activity in the H 3 R antagonists, ADS1017 and ADS1020 (Chart 1), and determined the influence of moving the benzyl-and 4-trifluoromethylbenzyl substituents from the N 1 to the N 3 position of the guanidine. 31 Finally, two s y m m e t r i c a l c o m p o u n d s , 1 , 4 -b i s { 4 -[ 1 -( 4trifluoromethylbenzyl)guandin-1-yl]but-1-yl}piperazine (ADS1030) and 1,4-bis(7-phenoxyheptyl)piperazine (ADS1031), were synthesized to identify the part of the parent compound that plays a key role in blocking H 3 R. The most potent derivatives we found had piperazine as a central core with disubstitution to N 1 of guanidine. 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.…”

“…This article describes the discovery of novel potent muscarinic receptor antagonists identified during a search for more active H 3 R ligands. Our previous study clarified whether both nitrogen atoms of the piperazine ring are necessary to maintain a high activity in the H 3 R antagonists, ADS1017 and ADS1020 (Chart ), and determined the influence of moving the benzyl- and 4-trifluoromethylbenzyl substituents from the N 1 to the N 3 position of the guanidine . Finally, two symmetrical compounds, 1,4-bis­{4-[1-(4-trifluoromethylbenzyl)­guandin-1-yl]­but-1-yl}­piperazine ( ADS1030 ) and 1,4-bis­(7-phenoxyheptyl)­piperazine ( ADS1031 ), were synthesized to identify the part of the parent compound that plays a key role in blocking H 3 R. The most potent derivatives we found had piperazine as a central core with disubstitution to N 1 of guanidine.…”

“…Finally, two symmetrical compounds, 1,4-bis­{4-[1-(4-trifluoromethylbenzyl)­guandin-1-yl]­but-1-yl}­piperazine ( ADS1030 ) and 1,4-bis­(7-phenoxyheptyl)­piperazine ( ADS1031 ), were synthesized to identify the part of the parent compound that plays a key role in blocking H 3 R. The most potent derivatives we found had piperazine as a central core with disubstitution to N 1 of guanidine. 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. , 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 ).…”