Triazolinone Biphenylsulfonamides as Angiotensin II Receptor Antagonists with High Affinity for Both the AT1 and AT2 Subtypes

Abstract

Angiotensin II (AII), the endogenous peptide ligand of the AII receptor, has equivalent high affinity for both the AT1 and AT2 receptor subtypes while most of the reported nonpeptide AII antagonists are AT1-selective. In an effort to identify dual AT1/AT2 nonpeptide AII antagonists, we have pursued modifications of previously prepared trisubstituted 1,2,4-triazolinone biphenylsulfonamides which exhibited subnanomolar in vitro AT1 (rabbit aorta) AII antagonism and AT2 (rat midbrain) IC50 values of < 40 nM. Present results show that a suitable amide (or reversed amide) side chain appropriately positioned on the N2-aryl group of these compounds gave > 15-fold enhancement in AT2 binding affinity without sacrificing nanomolar AT1 potency (IC50). This added amide, combined with an appropriate choice of the N-substituent on the sulfonamide and the ortho substituent on the N2-aryl group, led to an analogue (46, L-163,-007) which exhibited subnanomolar AT1 binding affinity and an AT2/AT1 IC50 ratio of 3. This compound showed excellent iv activity at 1 mg/kg and oral efficacy at 3 mg/kg with > 6 h duration in a conscious rat model. Available data suggest that the newly introduced amide side chain, mandatory for low nanomolar binding affinity at the AT2 receptor, is well-tolerated by the AT1 receptor and has minimal effect on the in vivo properties of these molecules.

1,2,4-Triazoles: Synthetic approaches and pharmacological importance. (Review)

“…Amidine and guanidine derivatives 9 (R = H·HCl, Me, CN) exhibiting a broad spectrum of antiviral activity [26] have been prepared. Some triazole derivatives are considered as angiotensin II receptor antagonists [27][28][29][30][31]. These compounds, such as 10 and 11, are used to increase the blood pressure.…”

4-Iodo-N-(o-tolylsulfonyl)benzamide

“…In recent years, N-(arylsulfonyl)-arylamides have received much attention as they constitute an important class of drugs for Alzheimer's disease (Hasegawa & Yamamoto, 2000), anti-bacterial inhibitors of tRNA synthetases (Banwell et al, 2000), antagonists for angiotensin II (Chang et al, 1994) and as leukotriene D4-receptors (Musser et al, 1990). Further, N-(arylsulfonyl)-arylamides are known as potent antitumour agents against a broad spectrum of human tumour xenografts (colon, lung, breast, ovary and prostate) in nude mice (Mader et al, 2005).…”

Development of CoMFA models of affinity and selectivity to angiotensin II type-1 and type-2 receptors

“…1) and 62 quinazolinones (cf. 2) [18][19][20][21][22][23][24][25]. We reviewed the literature and selected only those publications where the binding affinity of these compounds was measured by a single protocol and were derived from the same laboratory.…”