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

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.

Fine-tuning the selectivity of aldosterone synthase inhibitors: structure-activity and structure-selectivity insights from studies of heteroaryl substituted 1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-4-one derivatives.

Pyridine substituted 3,4-dihydro-1H-quinolin-2-ones (e.g., 1-3) constitute a class of highly potent and selective inhibitors of aldosterone synthase (CYP11B2), a promising target for the treatment of hyperaldosteronism, congestive heart failure, and myocardial fibrosis.

Theoretical studies on the interaction of partial agonists with the 5-HT2A receptor.

A series of 51 5-HT(2A) partial agonistic arylethylamines (primary or benzylamines) from different structural classes (indoles, methoxybenzenes, quinazolinediones) was investigated by fragment regression analysis (FRA), docking and 3D-QSAR approaches. The data, pEC(50) values and intrinsic activities (E(max)) on rat arteries, show high variability of pEC(50) from 4 to 10 and of E(max) from 15 to 70%. FRA indicates which substructures affect potency or intrinsic activity.

Selective aldosterone synthase inhibitors reduce aldosterone formation in vitro and in vivo.

Aldosterone plays a crucial role in salt and water homeostasis but in case of pathologically increased plasma aldosterone levels it is also involved in the development and the progression of severe cardiovascular diseases like heart failure and myocardial fibrosis. For the treatment of these diseases we propose inhibition of the aldosterone forming enzyme CYP11B2 as a new pharmacological strategy. We recently developed in vitro highly potent and selective inhibitors of human CYP11B2, but the evidence of their in vivo activity is still missing.

Novel aldosterone synthase inhibitors with extended carbocyclic skeleton by a combined ligand-based and structure-based drug design approach.

Pharmacophore modeling of a series of aldosterone synthase (CYP11B2) inhibitors triggered the design of compounds 11 and 12 by extending a previously established naphthalene molecular scaffold (e.g., present in molecules 1 and 2) via introduction of a phenyl or benzyl residue in 3-position.

Overcoming undesirable CYP1A2 inhibition of pyridylnaphthalene-type aldosterone synthase inhibitors: influence of heteroaryl derivatization on potency and selectivity.

Recently, we reported on the development of potent and selective inhibitors of aldosterone synthase (CYP11B2) for the treatment of congestive heart failure and myocardial fibrosis. A major drawback of these nonsteroidal compounds was a strong inhibition of the hepatic drug-metabolizing enzyme CYP1A2. In the present study, we examined the influence of substituents in the heterocycle of lead structures with a naphthalene molecular scaffold to overcome this unwanted side effect.

Expedient construction of the vibsanin E core without the use of protecting groups.

[reaction: see text] The tricyclic core of vibsanin E was constructed without the use of a protecting group in six steps. The El Gaïed Baylis-Hillman variant was key to allowing the Brønsted acid induced tandem cyclization forming rings B and C in one operation.

Unprecedented photochemical induced cascading rearrangement of the 3-azabicyclo[3.3.1]nonane skeleton.

Certain 3-azabicyclo[3.3.1]nonane derivatives undergo unprecedented stereospecific skeletal cleavage when subjected to light affording a novel heterotricyclic skeleton.