Interconversion of Functional Activity by Minor Structural Alterations in Nonpeptide AT₂ Receptor Ligands

Abstract

Migration of the methylene imidazole side chain in the first reported selective drug-like AT 2 receptor agonist C21/M024 (1) delivered the AT 2 receptor antagonist C38/M132 (2). We now report that the AT 2 receptor antagonist compound 4, a biphenyl derivative that is structurally related to 2, is transformed to the agonist 6 by migration of the isobutyl group. The importance of the relative position of the methylene imidazole and the isobutyl substituent is highlighted herein. KEYWORDS:AT 2 receptor, nonpeptide ligands, agonist, antagonist, C21/M024, C38/M132 T he sartans (angiotensin II receptor blockers, ABRs) have been on the market as antihypertensives for more than two decades and act as selective antagonists at the angiotensin II AT 1 receptor. More recently, the angiotensin AT 2 receptor has emerged as a new target for drug intervention.1−3 In 2004, the first selective and drug-like AT 2 receptor agonist C21/ M024 (1) was disclosed, 4 and thereafter, a series of structural analogues with agonistic properties have been reported. 5,6 The activation of the AT 2 receptor is known to render a large number of diverse biological responses. 7,8 For example, receptor activation stimulates neurite outgrowth in neuronal cells, which is one of the first steps in neuronal differentiation. 9In healthy adults the AT 2 receptor expression is low and mainly found in renal, cardiovascular, and brain tissues. 7,8 Notably, during certain pathological conditions, such as myocardial infarction, vascular injury, brain ischemia, renal failure, and cutaneous wounds, the AT 2 receptor expression is significantly up-regulated. 7,8 Recently, several studies conducted in experimental disease models have revealed that the selective potent AT 2 receptor agonist 1 acts as an anti-inflammatory agent and exerts pronounced tissue protective effects in particular in cardiovascular and renal disease. Hence, the compound has had a large impact on the view of the AT 2 receptor as a drug target.1,9−14 In addition, the AT 2 receptor is a promising drug target for antagonists. Thus, the AT 2 receptor antagonist EMA401 has demonstrated convincing efficacy data in patients suffering from neuropathic pain (postherpetic neuralgia) in a phase II study. 3 We discovered that migration of the methylene imidazole substituent of 1 from the para to the meta substitution pattern delivered a selective AT 2 receptor antagonist, compound C38/M132 (2) (Figure 1). 15,16 Thus, a minor structural alteration resulted in the interconversion of a selective AT 2 receptor agonist to a selective AT 2 receptor antagonist.Herein, we report the synthesis and biological evaluation of four AT 2 receptor ligands, the biphenyl derivatives, and regioisomers, 3, 4, 5, and 6 (Figure 2), and that the relative position of the imidazole and isobutyl substituent determines the functional outcome.The

High affinity rigidified AT2 receptor ligands with indane scaffolds

“…The antagonists 7b and 10a are indeed the first compounds to show K i values in the single digit nM range. 27,29 For comparison the AT2R antagonists 2 (C38/ M132) and 4 display K i values of 17.8 nM and 12.3 nM, respectively and PD123319 that is structurally very different from the ligands discussed herein exhibits an IC50 of 34 nM. 18,40 We have previously observed potent inhibition of Ang IIinduced neurite outgrowth from this class of AT 2 receptor antagonists at low concentrations, as compared to the corresponding K i -values.…”

“…We reported that independent of the methylene imidazole position, both an antagonist (4) and an agonist (6) could be obtained by moving the isobutyl side chain. 29 This suggests that the structural feature responsible for functionality is the spatial relationship between the imidazole ring and the isobutyl side chain.…”

“…1). 29 Furthermore, we reported that both compound 5 and 6 with the methylene imidazole group in the para position and in the meta position, respectively, exhibited agonism although their binding affinities to the AT 2 receptor were 10fold lower. Thus, the relative positions of the methylene imidazole and the isobutyl substituent seemed of importance in determining the functional activity of this class of selective AT 2 receptor biaryl derivatives (Fig.…”

“…1). 29 It can be hypothesized that the imidazole rings of 1-6 i.e. both agonists and antagonists, could bind to the same interaction point of the AT 2 receptor, while the isobutyl groups of agonists and antagonists are forced to be positioned differently and cause the difference in functionality observed.…”

Small‐molecule AT2 receptor agonists

“…Thus, migration of the isobutyl group of the antagonist 82 to yield compound 83 , regains the agonism. Compound 84 , where eight carbon atoms separate the two side chains serves as an agonist . However, there are exceptions to the hypothesis that a shorter distance between the side chains results in antagonism.…”