6-Substituted benzimidazoles as new nonpeptide angiotensin II receptor antagonists: synthesis, biological activity, and structure-activity relationships

Abstract

Starting from the recently reported nonpeptidic angiotensin II (AII) receptor antagonists DuP753 (1) and Exp 7711 (2), we have designed and investigated novel substituted benzimidazoles. Systemic variation of several substituents at the benzimidazole ring positions 4-7 led to the finding that substitution in position 6 with acylamino groups results in highly active AII antagonists. Compounds with 6-membered lactam or sultam substituents in position 6 of benzimidazole showed receptor activities in the low nanomolar range but were only weakly active when given orally to rats. In contrast, analogous substitution of the benzimidazole moiety with basic heterocycles resulted in potent AII antagonists which were also well absorbed after oral application. The most active compound of this series, 33 (BIBR 277), was selected as a candidate for clinical development. On the basis of molecular modeling studies a binding model of this new class of AII antagonists to the AT1 receptor is proposed.

Synthesis and biological activities of novel nonpeptide angiotensin II receptor antagonists based on benzimidazole derivatives bearing a heterocyclic ring

“…2-Cyano-4 0 -methylbiphenyl (5) was purchased from Aldrich. Preparation of 4 0 -methylbiphenyl-2-carboxylic acid (13) 23 and 2-n-Propyl-4-methyl-6-(1-methylbenzimidazol-2-y1)benzimidazole (25) 22 were performed according to reported procedures.…”

“…Thus, we started our investigation of replacement of the tetrazole ring in AngII receptor antagonists. Besides, the available data from the literature 22 indicated that a benzimidazole derivative, especially 'double benzimidazole', was an excellent group for good binding affinity. Thus, we wish to report herein our synthesis, and in vitro and in vivo biological evaluation of the designed benzimidazole derivatives bearing a heterocyclic ring (Chart 1).…”

Novel synthetic bisbenzimidazole that targets angiogenesis in Ehrlich ascites carcinoma bearing mice

“…[5][6][7] Multiple previous reports have suggested that benzimidazoles to be very good cytotoxic agents against different types of cancer cell lines. 8 Recently bisbenzimidazole conjugates have been reported to target mitochondria in cancer cells and induce their antiproliferative activity by caspase dependent apoptosis.…”

Rational design, efficient syntheses and biological evaluation of N , N ′-symmetrically bis-substituted butylimidazole analogs as a new class of potent Angiotensin II receptor blockers

“…Since then, numerous new antagonists have been reported by various research groups with nine of them in the clinic i.e. Candesartan [4], Valsartan [5], Irbesartan [6], Telmisartan [7], Olmesartan [8] which have been established as strong AT1 Receptor Blockers (ARBs). On 25 February 2011, the U.S. Food and Drug Administration (FDA) approved Azilsartan medoxomil [9,10] which is a newer-generation ARB, for the treatment of high blood pressure in adults.…”

“…Structure Activity Relationship (SAR) studies of Losartan and other imidazole blockers have been reported. Lipophilic substituents, such as the biphenylmethyl group at the 1-position [12], a linear alkyl group at the 2-position [13,14] and an acidic group, like tetrazole, CO 2 H, or NHSO 2 CF 3 on the biphenylmethyl group [4,7,15], are required for antagonistic activity. Furthermore, the DuPont group recommended a lipophilic and electron-withdrawing group, such as iodine or CF 3 , as a substituent at the 4-position and a smallsized group at the 5-position, such as CH 2 OH, CH 2 OMe, or CO 2 H, which is capable of forming a hydrogen bond [8,9].…”