Nonpeptide angiotensin II receptor antagonists. Synthesis and biological activity of benzimidazoles.
A series of substituted 2-butylbenzimidazoles bearing a biphenylylmethyl moiety at the 1-position was prepared via three synthetic routes and evaluated for angiotensin II (AII) receptor antagonistic activity (in vitro and in vivo). Binding affinity was determined using bovine adrenal cortical membrane. Substitution at the 4-, 5-, or 6-position reduced the affinity relative to that of the unsubstituted compound (13a). However, most of the compounds with a substituent at the 7-position showed binding affinity comparable to that of DuP 753 (losartan). In functional studies, a carboxyl group was found to be very important for antagonistic activity against AII. Comparison of 2-butyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]- 1H-benzimidazole-4-, -5-, -6-, and -7-carboxylic acids (15a-d) in an AII-induced rabbit aortic ring contraction assay clearly demonstrated the importance of the substitutional position of the carboxyl group. In an in vivo assay, oral administration of benzimidazole-7-carboxylic acids caused long-lasting inhibition of the AII-induced pressor response in rats. The optimum substituent at the 7-position of the benzimidazole ring was found to be a carboxyl or an ester group. The representative compound, 2-butyl-1-[[2'- (1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxy lic acid (15d, CV-11194), inhibited the specific binding of [125I]AII to bovine adrenal cortical membrane with an IC50 value of 5.5 x 10(-7) M. The AII-induced contraction of rabbit aortic strips was antagonized by CV-11194 (IC50 value, 5.5 x 10(-11) M), while the compound had no effect on the contraction induced by norepinephrine or KCl. Orally administered CV-11194 at doses of 0.3-10 mg/kg dose-dependently inhibited the AII-induced pressor response in rats and dogs. CV-11194 at 1 mg/kg po reduced blood pressure in spontaneously hypertensive rats (SHR). The three-dimensional molecular structure of CV-11194 was determined by X-ray diffraction.
Kubo
K
K
Pharmaceutical Research, Division, Takeda Chemical Industries, Ltd., Osaka, Japan.
Inada
Y
Y
Kohara
Y
Y
Sugiura
Y
Y
Ojima
M
M
Itoh
K
K
Furukawa
Y
Y
Nishikawa
K
K
Naka
T
T
D000302:Adrenal Cortex / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001011:Aorta / Q000502:physiology; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002417:Cattle; D004285:Dogs; D007093:Imidazoles / Q000494:pharmacology; D019808:Losartan; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects; D011817:Rabbits; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D014961:X-Ray Diffraction
D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D007093:Imidazoles; D013777:Tetrazoles; D000804:Angiotensin II; C081672:CV 11194; D019808:Losartan