Nonpeptide angiotensin II receptor antagonists. Synthesis and biological activity of benzimidazolecarboxylic acids

Abstract

A series of 2-substituted-1-[(biphenyl-4-yl)methyl]-1H-benzimidazole-7- carboxylic acids was prepared from the key intermediate 3-amino-2-[[(biphenyl-4- yl)methyl]amino]benzoate (6a-c) in order to clarify the structure-activity relationships of various analogues of 2-butyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-ben zimidazole- 7-carboxylic acid (CV-11194), a potent and long acting angiotensin II (AII) receptor antagonist. The AII antagonistic activity of the benzimidazoles was investigated by in vitro assays, which included an AII receptor binding assay and AII-induced vasocontraction assay, as well as by in vivo assays such as an AII-induced pressor response in rats. Most of the benzimidazoles showed high affinity for the AII receptor (IC50 value, 10(-6)-10(-7) M) and inhibited the AII-induced pressor response at 1 or 3 mg/kg po, and the effects were more potent than those of CV-11194 and DuP 753. The structure-activity relationship studies on the binding affinity and the inhibition of AII-induced pressor response suggested that straight chains of a certain length (e.g., ethoxy groups, ethyl groups) were the best as substituents at the 2-position and that their steric factors, lipophilicity, and electronic effects affected the potency of the AII antagonistic action. Both a carboxyl group at the 7-position and a tetrazole ring at the 2'-position were particularly important for potent and orally active AII antagonistic activity and a long-acting hypotensive effect. The representative compound, 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H- benzimidazole-7-carboxylic acid (26b, CV-11974), inhibited the specific binding of [125I]AII to bovine adrenal cortical membrane with an IC50 value of 1.1 x 10(-7) M. The AII-induced contraction of rabbit aortic strips was antagonized by CV-11974 (IC50 value, 3.0 x 10(-10) M). Oral administration of CV-11974 to conscious normotensive rats at 1 mg/kg resulted in long-lasting inhibition of the AII-induced pressor response. CV-11974 at 0.1-1 mg/kg iv reduced blood pressure dose-dependently in spontaneously hypertensive rats.

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

“…The organic layer was washed with H 2 O (2 Â 10 mL), dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, EtOAc/Hex 3:2) to afford the pure Z-and E-9 isomers as yellow oils (0.26 g and 0.10 g, respectively).…”

“…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].…”

Pharmacologic properties of candesartan cilexetil—possible mechanisms of long-acting antihypertensive action

“…[8][9][10][11] Candesartan cilexetil showed antihypertensive action in clinical trials and in animal models of hypertension. 6,7,12,13 In this report, we compare the duration of the antihypertensive effect of candesartan cilexetil with that of other AT 1 -receptor antagonists.…”

CV‐11974: A Nonpeptide Angiotensin II Type 1 Receptor Antagonist

“…In this review, we summarize the pharmacological characteristics of one AT, receptor antagonist, CV-11974, which was synthesized by Takeda Chemical Industries (Osaka, Japan) (14,21,29). The scientists at the Takeda Chemical Industries discovered the basic chemical structure of nonpeptide Ang I1 receptor antagonists in the late 1970s (US patents 4 340 598 and 4 355 040).…”