title: Identification, synthesis and pharmacological activity of moxonidine metabolites.
abstract: The metabolism of moxonidine, 4-chloro-N-(4,5-dihydro-1H-imidazol-2-yl)-6-methoxy-2-methyl-5-pyrimidinamine, LY326869, in rats, mice, dogs, and humans has been examined. At least 17 metabolites were identified or tentatively identified in the different species by HPLC, LC/MS and LC/MS/MS. The identities of seven of the major metabolites have been verified by independent synthesis. The metabolites are generally derived from oxidation and conjugation pathways. Oxidation occurred at the imidazolidine ring as well as the methyl at the 2 position of the pyrimidine ring. All seven metabolites were examined in the spontaneously hypertensive rats (3 mg kg(-1), i.v.) for pressure and heart rate. Only one, 2-hydroxymethyl-4-chloro-5-(imidazolidin-2-ylidenimino)-6-methoxypyrimidine, exerted a short-lasting decrease in blood pressure, albeit attenuated in magnitude compared to moxonidine.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Co., Lafayette, IN 47905, USA. wirth@lilly.com
authors.forename: David D
authors.initials: DD
authors.lastname: Wirth
authors.forename: Minxia M
authors.initials: MM
authors.lastname: He
authors.forename: Boris A
authors.initials: BA
authors.lastname: Czeskis
authors.forename: Karen M
authors.initials: KM
authors.lastname: Zimmerman
authors.forename: Ulrike
authors.initials: U
authors.lastname: Roettig
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Stenzel
authors.forename: Mitchell I
authors.initials: MI
authors.lastname: Steinberg
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D004285:Dogs; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D010084:Oxidation-Reduction; D051381:Rats; D011916:Rats, Inbred F344; D013329:Structure-Activity Relationship; D013997:Time Factors
chemical_list: D000959:Antihypertensive Agents; D007093:Imidazoles; C043482:moxonidine