title: Synthesis and stability in biological media of 1H-imidazole-1-carboxylates of ROS203, an antagonist of the histamine H3 receptor.
abstract: 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)-alpha-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.
authors.affiliation: Dipartimento Farmaceutico, Viale G. P. Usberti 27/a, I-43100 Parma.
authors.forename: Mirko
authors.initials: M
authors.lastname: Rivara
authors.forename: Federica
authors.initials: F
authors.lastname: Vacondio
authors.forename: Claudia
authors.initials: C
authors.lastname: Silva
authors.forename: Valentina
authors.initials: V
authors.lastname: Zuliani
authors.forename: Marco
authors.initials: M
authors.lastname: Fantini
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Bordi
authors.forename: Pier Vincenzo
authors.initials: PV
authors.lastname: Plazzi
authors.forename: Simona
authors.initials: S
authors.lastname: Bertoni
authors.forename: Vigilio
authors.initials: V
authors.lastname: Ballabeni
authors.forename: Lisa
authors.initials: L
authors.lastname: Flammini
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Barocelli
authors.forename: Marco
authors.initials: M
authors.lastname: Mor
mesh_terms: D000818:Animals; D052160:Benzothiazoles / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology*; D002264:Carboxylic Acids / Q000737:chemistry; D002384:Catalysis; D002417:Cattle; D004353:Drug Evaluation, Preclinical; D004355:Drug Stability; D004950:Esterases / Q000737:chemistry*; D054828:Histamine H3 Antagonists / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007093:Imidazoles / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007275:Injections, Intravenous; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D015394:Molecular Structure; D051381:Rats; D018100:Receptors, Histamine H3 / Q000187:drug effects*; D012710:Serum Albumin, Bovine / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013552:Swine
chemical_list: C527655:2-((2-(1H-imidazol-4-yl)ethyl)sulfanyl)-1,3-benzothiazole; D052160:Benzothiazoles; D002264:Carboxylic Acids; D054828:Histamine H3 Antagonists; D007093:Imidazoles; D018100:Receptors, Histamine H3; D012710:Serum Albumin, Bovine; D004950:Esterases