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 1 (AT 1) receptor and a K i value of 480 ± 110 nM for the AII subtype 2 (AT 2) receptor. BIBS 222 showed a K i value of 20 ± 7 nM for the AT 1 subtype and a K i value of 730 ± 170 nM for the AT 2 subtype. Thus BIBS 39 was 17 times more selective for the AT 1 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 pA 2 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 K B value of 9.01 (±3.22).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. BIBS 222 also caused parallel shifts to the right but a significant reduction of the maximal responses was observed at 3 and 10 mg/kg i.v. These results show that the benzimidazole derivatives BIBS 39 and BIBS 222 are potent and selective AII receptor antagonists. Substitution with a benzimidazole moiety results into a considerable loss of selectivity for the AT 1 receptor subtype compared with an imidazole moiety as, for instance, in DuP 753.