title: Pharmacological profile of ME3221, a novel angiotensin II receptor antagonist.
abstract: The pharmacological profile of a new surmountable angiotensin AT1 receptor antagonist, ME3221, 3-methoxy-2,6-dimethyl-4-[[2'-(1H-tetrazol-5-yl)-1,1'-biphenyl-4- yl]methoxy]pyridine, was studied in several animal models, and was compared with that of losartan. EF2831, 3-hydroxy-2,6-dimethyl-4-[[2'-(1H-tetrazol-5-yl)-1,1'-biphenyl-4- yl]methoxy]pyridine, a metabolite of ME3221, is also a surmountable angiotensin AT1 receptor antagonist, whose potency was 1/30 that of ME3221 in vitro, but equal to or 1/3 of that of ME3221 in in vivo experiments. In rats and marmosets, ME3221 antagonized angiotensin II-induced pressor responses, but did not affect bradykinin-induced depressor responses. ME3221 lowered the blood pressure in renal hypertensive rats and spontaneously hypertensive rats (SHR), and its ED25 value was 3 times that of losartan. Repeated administration of ME3221 to SHR had a stable and long-lasting antihypertensive effect without influencing heart rate. Thus ME3221, like losartan, may be useful in the treatment of renal and essential hypertension.
authors.affiliation: Drug Discovery Laboratories, Meiji Seika Kaisha, Ltd., Yokohama, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Nagura
authors.forename: S
authors.initials: S
authors.lastname: Yasuda
authors.forename: K
authors.initials: K
authors.lastname: Fujishima
authors.forename: M
authors.initials: M
authors.lastname: Yamamoto
authors.forename: C
authors.initials: C
authors.lastname: Hui
authors.forename: K
authors.initials: K
authors.lastname: Kawano
authors.forename: K
authors.initials: K
authors.lastname: Katano
authors.forename: H
authors.initials: H
authors.lastname: Ogino
authors.forename: M
authors.initials: M
authors.lastname: Hachisu
authors.forename: F
authors.initials: F
authors.lastname: Konno
mesh_terms: D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D001920:Bradykinin / Q000494:pharmacology; D002144:Callithrix; D004195:Disease Models, Animal; D004341:Drug Evaluation; D005260:Female; D005263:Femoral Artery / Q000187:drug effects / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D006977:Hypertension, Renal / Q000188:drug therapy; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D019808:Losartan; D008297:Male; D011817:Rabbits; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D007093:Imidazoles; C093897:ME 3221; D013777:Tetrazoles; D000804:Angiotensin II; C066026:losartan carboxylic acid; D019808:Losartan; D001920:Bradykinin