Intermolecular interactions involving aromatic rings are key processes in both chemical and biological recognition. Their understanding is essential for rational drug design and lead optimization in medicinal chemistry. Different approaches-biological studies, molecular recognition studies with artificial receptors, crystallographic database mining, gas-phase studies, and theoretical calculations-are pursued to generate a profound understanding of the structural and energetic parameters of individual recognition modes involving aromatic rings. This review attempts to combine and summarize the knowledge gained from these investigations. The review focuses mainly on examples with biological relevance since one of its aims it to enhance the knowledge of molecular recognition forces that is essential for drug development.

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Zwischenmolekulare Wechselwirkungen unter Beteiligung aromatischer Ringe sind Schlüsselvorgänge sowohl in chemischen als auch in biologischen Erkennungsprozessen. Ihr Verständnis ist für das rationale Wirkstoffdesign und für die Leitstrukturoptimierung in der Medizinischen Chemie essenziell. Unterschiedliche Ansätze werden für ein tiefergehendes Verständnis der strukturellen und energetischen Parameter einzelner Erkennungsarten mit aromatischen Substraten verfolgt: erwähnt seien biologische Untersuchungen, Studien der molekularen Erkennung mit künstlichen Rezeptoren, Suchen in kristallographischen Datenbanken, Gasphasenstudien und theoretische Untersuchungen. Dieser Aufsatz versucht, diese Wissensgebiete zu vereinen und die aus zahlreichen Untersuchungen gewonnenen Erkenntnisse zusammenzufassen. Er widmet sich hauptsächlich Beispielen mit biologischer Relevanz mit dem Ziel, die für die Wirkstoffentwicklung wichtigen Kenntnisse der molekularen Erkennung zu vertiefen.

Rationale: It has been proposed that an activated renin angiotensin system (RAS) causes an imbalance between the vasoconstrictive and vasodilator mechanisms involving the pulmonary circulation leading to the development of pulmonary hypertension (PH). Recent studies have indicated that angiotensin-converting enzyme 2 (ACE2), a member of the vasoprotective axis of the RAS, plays a regulatory role in lung pathophysiology, including pulmonary fibrosis and acute lung disease. Based on these observations, we propose the hypothesis that activation of endogenous ACE2 can shift the balance from the vasoconstrictive, proliferative axis (ACE-Ang II-AT1R) to the vasoprotective axis [ACE2-Ang-(1-7)-Mas] of the RAS, resulting in the prevention of PH. Objectives: We have taken advantage of a recently discovered synthetic activator of ACE2, XNT (1-[(2-dimethylamino) ethylamino]-4-(hydroxymethyl)-7-[(4-methylphenyl) sulfonyl oxy]-9H-xanthene-9-one), to study its effects on monocrotaline-induced PH in rats to support this hypothesis. Methods: The cardiopulmonary effects of XNT were evaluated in monocrotaline-induced PH rat model. Measurements and Main Results: A single subcutaneous treatment of monocrotaline in rats resulted in elevated right ventricular systolic pressure, right ventricular hypertrophy, increased pulmonary vessel wall thickness, and interstitial fibrosis. These changes were associated with increases in the mRNA levels of renin, ACE, angiotensinogen, AT1 receptors, and proinflammatory cytokines. All these features of PH were prevented in these monocrotaline-treated rats by chronic treatment with XNT. In addition, XNT caused an increase in the antiinflammatory cytokine, IL-10. Conclusions: These observations provide conceptual support that activation of ACE2 by a small molecule can be a therapeutically relevant approach for treating and controlling PH.Keywords: renin angiotensin system; angiotensin-converting enzyme 2; pulmonary heart disease.Pulmonary hypertension (PH) presents a diverse etiology and is defined by a mean pulmonary arterial pressure of greater than 25 mm Hg at rest, or greater than 30 mm Hg with exercise (1). The most common causes of PH include chronic obstructive pulmonary disease (often caused by smoking), left heart failure, substance abuse, schistosomiasis, high altitude exposure, drugs, toxins (e.g., chemical warfare), and HIV infection (2, 3). It has been proposed that these risk factors, coupled with predisposing genetic factors, lead to an imbalance between vasoconstrictor and vasodilator mechanisms. This imbalance initiates a cascade of pathophysiological events in the lungs leading to PH (4). These events are suggested to be set in motion by pulmonary vascular endothelial dysfunction causing enhanced proliferation and activation of lung fibroblasts, leading to extracellular matrix formation and fibrosis, infiltration of inflammatory cells, increased production of proinflammatory cytokines, exaggerated pulmonary vascular remodeling, and smooth muscle hypertrophy (5, 6). Vasodilatory ther...

Abstract-Angiotensin-converting enzyme 2 (ACE2) is a key renin-angiotensin system enzyme involved in balancing the adverse effects of angiotensin II on the cardiovascular system, and its overexpression by gene transfer is beneficial in cardiovascular disease. Therefore, our objectives were 2-fold: to identify compounds that enhance ACE2 activity using a novel conformation-based rational drug discovery strategy and to evaluate whether such compounds reverse hypertension-induced pathophysiologies. We used a unique virtual screening approach. In vitro assays revealed 2 compounds (a xanthenone and resorcinolnaphthalein) that enhanced ACE2 activity in a dose-dependent manner. Acute in vivo administration of the xanthenone resulted in a dose-dependent transient and robust decrease in blood pressure (at 10 mg/kg, spontaneously hypertensive rats decreased 71Ϯ9 mm Hg and Wistar-Kyoto rats decreased 21Ϯ8 mm Hg; PϽ0.05). Chronic infusion of the xanthenone (120 g/day) resulted in a modest decrease in the spontaneously hypertensive rat blood pressure (17 mm Hg; 2-way ANOVA; PϽ0.05), whereas it had no effect in Wistar-Kyoto rats. Strikingly, the decrease in blood pressure was also associated with improvements in cardiac function and reversal of myocardial, perivascular, and renal fibrosis in the spontaneously hypertensive rats. We conclude that structure-based screening can help identify compounds that activate ACE2, decrease blood pressure, and reverse tissue remodeling. Administration of ACE2 activators may be a valid strategy for antihypertensive therapy. T he recent discovery of angiotensin-converting enzyme (ACE) 2 1,2 and its role in the control of renin-angiotensin system activity is relevant as a potentially valuable target for antihypertensive therapies. ACE2 is a zinc-dependent monocarboxypeptidase that plays a central role in balancing vasoconstrictor and proliferative actions of angiotensin (Ang) II with the vasodilatory and antiproliferative effects of Ang-(1-7). 3 Altered expression of this enzyme is associated with cardiac, vascular, and renal dysfunctions. 4,5 In addition, blocking the synthesis of Ang II by Ang-converting enzyme inhibitors or its actions by Ang II receptor blockers has been shown to increase cardiac ACE2 expression. 6,7 Furthermore, overexpression of ACE2 by gene transfer 8 protects the heart from hypertension-induced cardiac remodeling. It was demonstrated that ACE2 is an effective enzyme in attenuating fibrosis and structural remodeling. 8 Based on these observations, we hypothesize that pharmacological enhancement of ACE2 activity would have beneficial effects on the cardiovascular system and would protect against hypertensioninduced pathophysiology. Therefore, our objectives in this study were 2-fold: to identify compounds that enhance ACE2 activity and to determine the effects of ACE2 enhancers on hypertension and associated pathophysiology. Materials and MethodsSynthesis of xanthenone, measurement of ACE2 activity, histological analysis, and statistical analysis are described in the sup...