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Synthesis and Stability in Biological Media of 1 H ‐Imidazole‐1‐carboxylates of ROS203, an Antagonist of the Histamine H 3 Receptor
Author(s) -
Rivara Mirko,
Vacondio Federica,
Silva Claudia,
Zuliani Valentina,
Fantini Marco,
Bordi Fabrizio,
Plazzi Pier Vincenzo,
Bertoni Simona,
Ballabeni Vigilio,
Flammini Lisa,
Barocelli Elisabetta,
Mor Marco
Publication year - 2008
Publication title -
chemistry and biodiversity
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.427
H-Index - 70
eISSN - 1612-1880
pISSN - 1612-1872
DOI - 10.1002/cbdv.200890004
Subject(s) - chemistry , stereochemistry , lipophilicity , esterase , enzyme , enzymatic hydrolysis , bovine serum albumin , imidazole , hydrolysis , organic chemistry , chromatography
A series of carbamate derivatives of the H 3 antagonist ROS203 ( 1 ) were prepared, and their lipophilicity and steric hindrance were modulated by introducing linear or branched alkyl chains of various lengths. In vitro stability studies were conducted to evaluate how structural modulations affect the intrinsic reactivity of the carbamoyl moiety and its recognition by metabolic enzymes. Linear alkyl carbamates were the most susceptible to enzymatic hydrolysis, with bioconversion rates being higher in rat liver and plasma. Chain ramification significantly enhanced the enzymatic stability of the set, with two derivatives ( 1g and 1h ) being more stable by a factor of 8–40 than the ethyl carbamate 1a . Incubation with bovine serum albumin (BSA) showed a protective role of proteins on chemical and porcine‐liver esterase (PLE)‐catalyzed hydrolysis. Ex vivo binding data after i.v. administration of 1h revealed prolonged displacement of the labeled ligand [ 3 H]‐( R )‐ α ‐methylhistamine ([ 3 H]RAMHA) from rat‐brain cortical membranes, when compared to 1 . However, the high rates of bioconversion in liver, as well as the chemical instability of 1h , suggest that further work is needed to optimize the enzymatic and chemical stability of these compounds.