Novel Pyridyl- or Isoquinolinyl-Substituted Indolines and Indoles as Potent and Selective Aldosterone Synthase Inhibitors

Yin, Lina; Hu, Qingzhong; Emmerich, Juliette; Lo, Michael Man‐Chu; Metzger, E. Joseph; Ali, Amjad; Hartmann, Rolf W.

doi:10.1021/jm500140c

Cited by 45 publications

(28 citation statements)

References 47 publications

(39 reference statements)

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“…12 A series of novel pyridyl-or isoquinolinyl-substituted indolines and indoles have recently been synthesized using a ligand-based approach. These compounds are as potent and more selective than LCI699 for CYP11B2 over CYP11B1 14,44 and are currently being tested as treatments for mineralocorticoid-dependent CVD and renal disease.…”

Section: Aldosterone Synthase Inhibitorsmentioning

confidence: 99%

“…Intraperitoneal injection of C-ANP [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] has been shown to decrease BP in SHR by inhibiting enhanced expression of Giα proteins and reducing nitrooxidative stress, not by modulating the eNOS/cyclic guanosine monophosphate pathway. This study revealed a novel function of NPR-C, which has generally been considered a clearance receptor for natriuretic peptides and has raised the possibility that NPR-C agonists, such as C-ANP 4-23 , could be useful for the treatment of hypertension and related CVDs.…”

Section: Natriuretic Peptide Receptor Agonistsmentioning

confidence: 99%

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New Approaches in the Treatment of Hypertension

Oparil

Schmieder

2015

Circulation Research

229

133

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Hypertension is the most common modifiable risk factor for cardiovascular disease and death, and lowering blood pressure with antihypertensive drugs reduces target organ damage and prevents cardiovascular disease outcomes. Despite a plethora of available treatment options, a substantial portion of the hypertensive population has uncontrolled blood pressure. The unmet need of controlling blood pressure in this population may be addressed, in part, by developing new drugs and devices/procedures to treat hypertension and its comorbidities. In this Compendium Review, we discuss new drugs and interventional treatments that are undergoing preclinical or clinical testing for hypertension treatment. New drug classes, eg, inhibitors of vasopeptidases, aldosterone synthase and soluble epoxide hydrolase, agonists of natriuretic peptide A and vasoactive intestinal peptide receptor 2, and a novel mineralocorticoid receptor antagonist are in phase II/III of development, while inhibitors of aminopeptidase A, dopamine β-hydroxylase, and the intestinal Na + /H + exchanger 3, agonists of components of the angiotensin-converting enzyme 2/angiotensin(1–7)/Mas receptor axis and vaccines directed toward angiotensin II and its type 1 receptor are in phase I or preclinical development. The two main interventional approaches, transcatheter renal denervation and baroreflex activation therapy, are used in clinical practice for severe treatment resistant hypertension in some countries. Renal denervation is also being evaluated for treatment of various comorbidities, eg, chronic heart failure, cardiac arrhythmias and chronic renal failure. Novel interventional approaches in early development include carotid body ablation and arteriovenous fistula placement. Importantly, none of these novel drug or device treatments has been shown to prevent cardiovascular disease outcomes or death in hypertensive patients.

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Section: Aldosterone Synthase Inhibitorsmentioning

confidence: 99%

Section: Natriuretic Peptide Receptor Agonistsmentioning

confidence: 99%

New Approaches in the Treatment of Hypertension

Oparil

Schmieder

2015

Circulation Research

229

133

View full text Add to dashboard Cite

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“…Recent identification of novel compounds namely pyridyl- or isoquinolinyl-substituted indolines and indoles, with greater selectivity for aldosterone synthase and prolonged half-life, has triggered new trials in the field of mineralocorticoid pathway-related cardio-renal disease. 85 The recent conclusion from the PATHWAY 2 trial that Spironolactone was the most effective add-on drug for the treatment of resistant hypertension reinforces the importance of the aldosterone pathway in the pathophysiology of hypertension and extra-renal conditions. 86 …”

Section: Old Systems Revisited: the Renin–angiotensin–aldosterone Systemmentioning

confidence: 99%

Interventional procedures and future drug therapy for hypertension

2016

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Hypertension management poses a major challenge to clinicians globally once non-drug (lifestyle) measures have failed to control blood pressure (BP). Although drug treatment strategies to lower BP are well described, poor control rates of hypertension, even in the first world, suggest that more needs to be done to surmount the problem. A major issue is non-adherence to antihypertensive drugs, which is caused in part by drug intolerance due to side effects. More effective antihypertensive drugs are therefore required which have excellent tolerability and safety profiles in addition to being efficacious. For those patients who either do not tolerate or wish to take medication for hypertension or in whom BP control is not attained despite multiple antihypertensives, a novel class of interventional procedures to manage hypertension has emerged. While most of these target various aspects of the sympathetic nervous system regulation of BP, an additional procedure is now available, which addresses mechanical aspects of the circulation. Most of these new devices are supported by early and encouraging evidence for both safety and efficacy, although it is clear that more rigorous randomized controlled trial data will be essential before any of the technologies can be adopted as a standard of care.

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“…The CYP11B2 crystal (PDB ID: 4DVQ) was processed as described previously, [43] including the removal of redundant protein copies, substrate and water as well as the addition of hydrogens and partial charges. Ligand was built and its energy was minimized in the MMFF94s force field using MOE.…”

Section: Docking Studymentioning

confidence: 99%

1-Phenylsulfinyl-3-(pyridin-3-yl)naphthalen-2-ols: A new class of potent and selective aldosterone synthase inhibitors

Grombein

Heim

et al. 2015

European Journal of Medicinal Chemistry

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1 Abstract 1-Phenylsulfinyl-3-(pyridin-3-yl)naphthalen-2-ols and related compounds were synthesized and evaluated for inhibition of aldosterone synthase (CYP11B2), a potential target for cardiovascular diseases associated with elevated plasma aldosterone levels like congestive heart failure and myocardial fibrosis. Introduction of substituents at the phenylsulfinyl moiety and changes of the substitution pattern at the naphthalene core were examined. Potent compounds were further examined for selectivity versus other important steroidogenic CYP enzymes, i.e. the highly homologous 11β-hydroxylase (CYP11B1), CYP17 and CYP19. The most potent compound (IC 50 = 14 nM) discovered was the metatrifluoromethoxy derivative 11, which also exhibited excellent selectivity toward CYP11B1 (SF = 415), and showed no inhibition of CYP17 and CYP19.

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Novel Pyridyl- or Isoquinolinyl-Substituted Indolines and Indoles as Potent and Selective Aldosterone Synthase Inhibitors

Cited by 45 publications

References 47 publications

New Approaches in the Treatment of Hypertension

New Approaches in the Treatment of Hypertension

Interventional procedures and future drug therapy for hypertension

1-Phenylsulfinyl-3-(pyridin-3-yl)naphthalen-2-ols: A new class of potent and selective aldosterone synthase inhibitors

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