75614-87-8Relevant academic research and scientific papers
Enzyme-catalyzed prodrug approaches for the histamine H3-receptor agonist (R)-α-methylhistamine
Stark, Holger,Krause, Michael,Rouleau, Agnes,Garbarg, Monique,Schwartz, Jean-Charles,Schunack, Walter
, p. 191 - 198 (2007/10/03)
Five novel prodrug types of the potent and selective histamine H3-receptor agonist (R)-α-methylhistamine (1) were prepared and pharmacologically tested in vitro as well as in vivo. In particular, an amide of fatty acid, mono- and dicarbamates, an (acyloxy)alkylcarbamate, and a diphthalidyl derivative were synthesized, all of which require initial prodrug activation through an enzyme-catalyzed reaction in contrast to formerly developed azomethine prodrugs which are cleaved by chemical hydrolysis only. Further drug liberation may ensue spontaneously in a cascade to give 1. Since they have diverse stabilities the prodrugs were investigated for drug liberation in vitro under neutral, acidic, and basic conditions at different temperatures as well as with liver homogenates. In vivo investigation of prodrugs after oral administration to mice proved that the fatty amide 2, the Nα-methylcarbamate 4a, and the Nα-(1-(acetyloxy)ethylcarbamate) 5 showed moderate to high plasma levels of 1. Compound 5 displayed even more than 2.5 times the AUC for 1 than that of the reference azomethine prodrug BP2.94 in the periphery and also displayed a detectable drug level in the central nervous system. It was shown that prodrug approaches based on an initial enzyme-catalyzed liberation step are successfully applicable to different pro-moieties for improved bioavailability and prolonged half-live. These approaches may also be used for other aminergic compounds of this class to optimize pharmacokinetic behavior.
New potent azomethine prodrugs of the histamine H3-receptor agonist (R)-α-methylhistamine1 containing a heteroarylphenyl partial structure
Krause, Michael,Rouleau, Agnes,Stark, Holger,Luger, Peter,Garbarg, Monique,Schwartz, Jean-Charles,Schunack, Walter
, p. 209 - 215 (2007/10/03)
The therapeutic value of histamine H3-receptor ligands is under current investigation. On the basis of recently described diaryl imine prodrugs of the histamine H3-receptor agonist (R)-α-methylhistamine (1) a series of new azomethine prodrugs containing five-and six-membered heterocycles were synthesized and tested for their in vitro hydrolysis rates and in vivo activity after oral application. It was found that electron-deficient six-membered heterocycles drastically destabilized the imine double bond so that these prodrugs decomposed unsuitably fast. On the contrary, prodrugs containing five-membered heterocycles appeared to be highly effective for the CNS delivery of 1, and a remarkable correlation between chemical structure and pharmacokinetic profile was observed. Particularly (R)-4-fluoro-2-[[N-[1-(1H-imidazol-4-yl)-2-propyl]imino](1H-pyrrol-2-yl)methyl] phenol (8c), the 2-furanyl analogue 8d, and its 3-furanyl isomer 8e proved to be equipotent to the most potent of recently described halogenated diaryl imine prodrugs of 1. However, in contrast to any other azomethine prodrug, 8c exhibited an incomparably long lasting delivery of 1 in the CNS and can thus be regarded as a 'retard' prodrug. Assuming that a therapeutic indication of histamine H3-receptor agonists will soon be established, these highly potent heteroarylphenyl azomethine prodrugs, which already serve as valuable pharmacological tools, may also become potential drugs in clinical use.
Structure-activity relationships of novel azomethine prodrugs of the histamine H3-receptor agonist (R)-α-methylhistamine: From alkylaryl to substituted diaryl derivatives
Krause,Rouleau,Stark,Garbarg,Schwartz,Schunack
, p. 720 - 726 (2007/10/03)
This study was performed on the basis of recently developed prodrugs of the histamine H3-receptor agonist (R)-α-methylhistamine (1) to determine structure-activity relationships of azomethine prodrugs of 1, in which the primary amine functionality is bioreversibly linked to aromatic ketones. Therefore, the pro-moiety was systematically altered from alkylaryl over benzylaryl to diaryl substitution. Those compounds that emerged to be stable enough during preparation were tested for their in vitro hydrolysis rates. Apparently, bulky alkyl residues were capable of preventing previously observed intramolecular cyclization, but the obtained azomethines 12 a-c were far too unstable to serve as prodrugs. However, the benzylaryl imines 12d, e were stable compounds, but 12d decomposed too rapidly under in vitro conditions. Distinctly greater stability was provided by diaryl pro-moieties, even if strongly electron-withdrawing functionalities were introduced. Selected compounds were also tested in vivo following p.o. application to mice. Particularly the trifluoromethyl substituted imine 12i proved to be highly effective as stability and rate of conversion were well-balanced, so that brain penetration of 1 was strikingly facilitated. Thus 12i, a highly potent azomethine prodrug, may serve as an important pharmacological tool and, possibly, a therapeutic agent.
Histamine analogues. 32nd communication: synthesis and pharmacology of sopromidine, a potent and stereoselective isomer of the achiral H2-agonist impromidine
Elz, Sigurd,Gerhard, Guenter,Schunack, Walter
, p. 259 - 262 (2007/10/02)
Synthesis and pharmacology of sopromidine ((R)-7) and (S)-7, 2 position isomers of impromidine derived from the enantiomeric α-methylhistamines, are reported.The enantiomers of 7 show high stereoselectivity at the atrial H2-receptor of the guinea-pig. (R)-7 is revealed to be a full H2-agonist with 7.4-fold potency relative to histamine, while (S)-7 is a competitive H2-antagonist. chiral H2-agonists / histamine H2-receptor / impromidine analogues / α-methylhistamine
