Design, Synthesis, and Structure−Activity Relationships of Novel Non-Imidazole Histamine H₃ Receptor Antagonists

Abstract

Novel, potent, and selective non-imidazole histamine H(3) receptor antagonists have been prepared based on the low-affinity ligand dimaprit (pK(I) 7.32 +/- 0.12, pK(B) 5.93 +/- 0.17). Detailed structure-activity studies have revealed that N-(4-chlorobenzyl)-N-(6-pyrrolidin-1-ylhexyl)guanidine (pK(I) 8.38 +/- 0.21, pK(B) 8.39 +/- 0.13), 30, and N-(4-chlorobenzyl)-N-(7-pyrrolidin-1-ylheptyl)guanidine (pK(I) 8.78 +/- 0.12, pK(B) 8.38 +/- 0.10), 31, exhibit high affinity for the histamine H(3) receptor. Antagonists 30 and 31 demonstrate significant selectivity over the other histamine, H(1) and H(2), receptor subtypes and a 100-fold selectivity in the sigma(1) binding assay. Compounds 30and 31 are the most potent, selective non-imidazole histamine H(3) receptor antagonists reported in the literature to date.

Two Novel and Selective Nonimidazole Histamine H3 Receptor Antagonists A-304121 and A-317920: I. In Vitro Pharmacological Effects

“…These compounds potently and selectively bind to the rat H 3 R with affinities comparable to those of the imidazole H 3 R antagonists thioperamide and ciproxifan. Additionally, A-304121 and A-317920 have equal or greater rat or guinea pig H 3 R affinities than several other non-imidazole series Walczynski et al, 1999a,b;Linney et al, 2000;Lazewska et al, 2001;Meier et al, 2001). Like many of the imidazole H 3 R antagonists, A-304121 and A-317920 are potent at rat H 3 R, but are considerably less potent at human H 3 R. It remains to be seen if this is also true of other non-imidazole H 3 R antagonists described previously.…”

“…Thus, it is desirable to synthesize potent and selective non-imidazole H 3 R antagonists as potential therapeutic agents in man. Recent reports from our laboratory (Faghih et al, 2002a,b) and from other groups Walczynski et al, 1999a,b;Linney et al, 2000;Lazewska et al, 2001;Meier et al, 2001) have described the properties of novel nonimidazole H 3 R antagonists. Herein, we describe the in vitro pharmacological profile of two non-imidazole, aryloxyalkyl piperazine-based H 3 R antagonists, A-304121 [4-(3-((2R)-2-aminopropanoyl-1-piperazinyl)propoxy)phenyl) cyclopropylmethanone] and A-317920 [N-((1R)-2-(4- (3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)-1-methyl-2-oxo-ethyl)-2-furamide] (Fig.…”

Design, synthesis, and evaluation of estradiol-linked genotoxicants as anti-cancer agents

“…Compound 5 was prepared by conversion alcohol 2 to the bromide, which was allowed to react with a protected ethanolamine providing 3 as described in reference 10. The Mitsunobo reaction 7 then was used to couple 1,3-bis(tertbutoxycarbonyl)-2-methyl-2-thiopseudourea with 3. Reaction of the resulting product 4 with excess (N,N-bis-2-chloroethylaminophenyl)-propylamine followed by acid deprotection produced 5.…”

“…Reaction of the resulting product 4 with excess (N,N-bis-2-chloroethylaminophenyl)-propylamine followed by acid deprotection produced 5. Procedures described by Litmey et al 7 were applied to incorporate an N,Ndisubstituted guanidine moiety into the linker. The preparation of 7 proceeded with the initial reaction of 2 with 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea under Mitsunobu conditions.…”

Synthesis of Novel Phosphorylated Guanidine Derivatives from Cyanamide and Their Anti-inflammatory Activity

“…4) The guanidine derivatives exhibited diverse biological and pharmacological activities such as neuronal Na + and Ca 2+ channel blockers, 5) glutamate release inhibitors, anti-ischemic agents, 6) anti-seizure agents, 7) aderenergic neuron-blocking agents, 8) human immunodeficiency virus-1 (HIV-1) protease inhibitors, 9) K + /ATP channel openers, nitric oxide (NO) synthase inhibitors, influenza neuraminidase inhibitors, 10) cardiotonic agents, 11) and histamine H 3 receptor antagonists. 12) Therefore, the guanidine functional group is an attractive pharmacophore for the development of novel drugs against tumors, hypertension, glaucoma, and inflammation. 13) We previously reported that phosphorylation of various drugs improves their biological activity.…”