The discovery of potent nonpeptide angiotensin II receptor antagonists: a new class of potent antihypertensives

Abstract

A new class of potent antihypertensives has been discovered that exert their effect through blockade of the angiotensin II (AII) receptor. Most AII antagonists reported so far are peptide mimics of the endogenous vasoconstrictor octapeptide angiotensin II. The compounds of this paper are nonpeptides and therefore constitute a new class of potent AII receptor antagonists. Based on the overlap of a conformation of AII with literature lead 3, a hypothesis was developed suggesting the need for an additional acidic functionality to increase the lead's potency. The substitution of an additional carboxylic acid resulted in a 10-fold increase in binding affinity observed for diacid 4. The binding affinities for subsequent compounds were eventually increased 1000-fold over that of the literature leads through a systematic SAR study. Thus the AII receptor binding affinity [IC50 (microM)] of 15 microM for literature lead 1, for example, was increased to 0.018 and 0.012 microM for compounds 33 and 53. A structure-affinity relationship has been found requiring the presence of four key elements for good activity: (1) an additional phenyl ring at the N-benzyl para position of the benzylimidazole nucleus, (2) an acidic functionality at the ortho position of the terminal aromatic ring, (3) a lipophilic side chain at the imidazole 2-position of three to five carbon atoms in length, and (4) a group at the imidazole 5-position capable of hydrogen bonding. The synthesis as well as the pharmacological activity of the compounds in this new series of AII receptor antagonists are presented.

Comparative study to evaluate efficacy and safety of azilsartan and telmisartan in patients with grade I-II essential hypertension

“…The development of AT1 receptor blockers (ARBs) can be traced back to the pioneer work of scientist at Takeda pharmaceutical who described a series of benzylimidazole compounds that inhibited the ability of angiotensin to stimulate the vascular contraction and increase blood pressure (BP). [22][23][24][25] More than 15 years after the clinical introduction of Losartan, the FDA approved Takeda's azilsartan medoxomil as the 8th ARB for the treatment of hypertension. 26 Azilsartan was discovered by modifying the tetrazole ring present in candesartan.…”

Comparative study of efficacy and adverse effects profile of azilsartan, olmesartan and candesartan in the control of essential hypertension

“…The development of AT1 receptor blockers (ARBs) can be traced back to the pioneer work of scientist at Takeda pharmaceutical who described a series of benzylimidazole compounds that inhibited the ability of angiotensin to stimulate the vascular contraction and increase blood pressure (BP). [16][17][18][19] More than 15 years after the clinical introduction of Losartan, the FDA approved Takeda's azilsartan medoxomil as the 8 th ARB for the treatment of hypertension. 20 Azilsartan was discovered by modifying the tetrazole ring present in candesartan.…”

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 latter was subjected to catalytic hydrogenation under H 2 atmosphere (3 bar) in the presence of Pd/C at ambient temperature for 2 h to give 4a in 92% yield. Finally, demasking of NH by treatment with 20% TFA in CH 2 Cl 2 in the presence of Et 3 SiH as scavenger furnished the target 4(5)-butylimidazole (5a).…”

“…Consequently, the RAS has been the prime target for the therapy of cardiovascular diseases and non-peptide AT1 receptor antagonists have been developed to specifically block it [1,2]. In specific, the DuPont group pursued a study in this field and developed Losartan, the first orally effective non-peptide antagonist, which is in vivo metabolized to the more potent EXP 3174 [3] ( Fig. 1).…”

“…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].…”