title: Characterization of BIBS 39 and BIBS 222: two new nonpeptide angiotensin II receptor antagonists.
abstract: Two new nonpeptide angiotensin II (AII) receptor antagonists, 4'-[(2-n-butyl-6-cyclohexylaminocarbonylamino-benzimidazole-1-yl)- methyl ] biphenyl-2-carboxylic acid (BIBS 39) and 2-n-butyl-1-[4-(6-carboxy-2,5-dichlorobenzoylamino)-benzyl]-6-N- (methylaminocarbonyl)-n-pentylamino-benzimidazole (BIBS 222) were characterized in radioligand binding assays, and in vitro and in vivo experiments. BIBS 39 displaced [125I] AII from its specific binding sites with a K(i) value of 29 +/- 7 nM for the AII subtype I (AT1) receptor and a K(i) value of 480 +/- 110 nM for the AII subtype 2 (AT2) receptor. BIBS 222 showed a K(i) value of 20 +/- 7 nM for the AT1 subtype and a K(i) value of 730 +/- 170 nM for the AT2 subtype. Thus BIBS 39 was 17 times more selective for the AT1 subtype and BIBS 222 37 times. Both compounds were specific for AII receptors as they did not show high affinity for other receptors. BIBS 39 shifted the AII concentration-contractile response curves in isolated rabbit aorta to the right in a parallel fashion. A pA2 value of 8.14 +/- 0.08 and a slope of 1.06 +/- 0.07 were calculated. BIBS 222 caused nonparallel shifts to the right and reduced the maximal response induced by AII by about 25%. A KB value of 9.01 (+/- 3.22) x 10(-8) M was determined. At 10(-5) M, neither compounds altered the contractile responses to noradrenaline and KCl. In pithed rats, BIBS 39 dose dependently shifted the dose-response curve of AII to the right without affecting the maximal response.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Pharma Research, Dr. Karl Thomae GmbH, Biberach/Riss, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.forename: M
authors.initials: M
authors.lastname: Entzeroth
authors.forename: W
authors.initials: W
authors.lastname: Wienen
authors.forename: J C
authors.initials: JC
authors.lastname: Van Meel
mesh_terms: D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D019808:Losartan; D008297:Male; D008782:Methylurea Compounds / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D011945:Receptors, Angiotensin / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D007093:Imidazoles; D008782:Methylurea Compounds; D011945:Receptors, Angiotensin; D013777:Tetrazoles; C077352:BIBS 39; C077353:BIBS 222; D019808:Losartan