title: Synthesis and pharmacological activity of the metabolites of Pratosartan.
abstract: Three hydroxylated metabolites of 2-propyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-5,6,7,8-tetrahydro-3H-cycloheptimidazol-4-one (Pratosartan), which is a selective angiotensin II receptor antagonist, were synthesized in confirmation of their structures and in studies of their pharmacological properties. An MTPA ester of the human main metabolite was identified with the synthesized compound by comparing (1)H-NMR spectra, MS spectra, and HPLC retention time. The structure of the human main metabolite was confirmed to be (S)-(-)-2-(1-hydroxypropyl)-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-5,6,7,8-tetrahydro-3H-cycloheptimidazol-4-one ((S)-(-)-1). Also, the rat main metabolites were confirmed to be 8-hydroxylated compound (2) and 5-hydroxylated compound (3). These metabolites showed lower antagonistic activity than that of the parent compound.
authors.affiliation: Kotobuki Research Laboratories, Kotobuki Seiyaku Company, Ltd, Sakaki-Machi, Nagano 389-0697, Japan. ktb-g121@kotobuki-pharm.co.jp
authors.forename: Motoharu
authors.initials: M
authors.lastname: Sonegawa
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Suzaka
authors.forename: Akira
authors.initials: A
authors.lastname: Tomiyama
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Tomiyama
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000302:isolation & purification*; D000818:Animals; D002250:Carbon Radioisotopes; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D007093:Imidazoles / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D015394:Molecular Structure; D051381:Rats; D053719:Tandem Mass Spectrometry / Q000379:methods; D013777:Tetrazoles / Q000378:metabolism*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D002250:Carbon Radioisotopes; D007093:Imidazoles; D013777:Tetrazoles; C528642:pratosartan