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1.
Eur J Med Chem ; 152: 53-64, 2018 May 25.
Article in English | MEDLINE | ID: mdl-29689474

ABSTRACT

In mammalian cells, aberrant iNOS induction may have detrimental consequences, and seems to be involved in the proliferation and progression of different tumors, such as malignant gliomas. Therefore, selective inhibition of iNOS could represent a feasible therapeutic strategy to treat these conditions. In this context, we have previously disclosed new acetamidines able to inhibit iNOS with a very high selectivity profile over eNOS or nNOS. Here we report the synthesis of a new series of compounds structurally related to the leading scaffold of N-[(3-aminomethyl)benzyl] acetamidine (1400 W), together with their in vitro activity and selectivity. Compound 39 emerged as the most promising molecule of this series, and it was ex vivo evaluated on isolated and perfused resistance arteries, confirming a high selectivity toward iNOS inhibition. Moreover, C6 rat glioma cell lines biological response to 39 was investigated, and preliminary MTT assay showed a significant decrease in cell metabolic activity of C6 rat glioma cells. Finally, results of a docking study shed light on the binding mode of 39 into NOS catalytic site.


Subject(s)
Antineoplastic Agents/pharmacology , Drug Discovery , Enzyme Inhibitors/pharmacology , Glioma/drug therapy , Nitric Oxide Synthase Type II/antagonists & inhibitors , Proline/analogs & derivatives , Amidines , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Cycle/drug effects , Cell Proliferation/drug effects , Cells, Cultured , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Glioma/metabolism , Glioma/pathology , Male , Mesenteric Arteries/drug effects , Mesenteric Arteries/metabolism , Molecular Docking Simulation , Molecular Structure , Nitric Oxide Synthase Type II/metabolism , Proline/chemical synthesis , Proline/chemistry , Proline/pharmacology , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship
2.
ChemMedChem ; 11(16): 1695-9, 2016 08 19.
Article in English | MEDLINE | ID: mdl-27377568

ABSTRACT

Nitric oxide (NO) is an essential endogenous mediator with a physiological role in the central nervous system as neurotransmitter and neuromodulator. A growing number of studies have demonstrated that abnormal nitrergic signaling is a crucial event in the development of neurodegeneration. In particular, the uncontrolled production of NO by neuronal nitric oxide synthase (nNOS) is observed in several neurodegenerative diseases. Moreover, it is well recognized that specific isoforms of human carbonic anhydrase (hCA) physiologically modulate crucial pathways of signal processing and that low expression of CA affects cognition, leading to mental retardation, Alzheimer's disease, and aging-related cognitive impairments. In light of this, dual agents that are able to target both NOS (inhibition) and CA (activation) could be useful drug candidates for the treatment of Alzheimer's disease, aging, and other neurodegenerative diseases. In the present work, we show the design, synthesis, and in vitro biological evaluation of new nitrogen-based heterocyclic compounds. Among the tested molecules, 2-amino-3-(4-hydroxyphenyl)-N-(1H-indazol-5-yl)propanamide hydrochloride (10 b) was revealed to be a potent dual agent, able to act as a selective nNOS inhibitor and activator of the hCA I isoform.


Subject(s)
Carbonic Anhydrase I/metabolism , Enzyme Inhibitors/pharmacology , Indazoles/pharmacology , Nitric Oxide Synthase Type I/antagonists & inhibitors , Oxazoles/pharmacology , Pyrazoles/pharmacology , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Indazoles/chemical synthesis , Indazoles/chemistry , Molecular Structure , Nitric Oxide Synthase Type I/metabolism , Oxazoles/chemical synthesis , Oxazoles/chemistry , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Structure-Activity Relationship
3.
Bioorg Med Chem Lett ; 26(13): 3192-3194, 2016 07 01.
Article in English | MEDLINE | ID: mdl-27161804

ABSTRACT

The most frequently used treatment for hormone receptor positive breast cancer in post-menopausal women are aromatase inhibitors. In order to develop new aromatase inhibitors, we designed and synthesized new imidazolylmethylpiperidine sulfonamides using the structure of the previously identified aromatase inhibitor SYN 20028567 as starting lead. By this approach, three new aromatase inhibitors with IC50 values that are similar to that of letrozole and SYN 20028567 were identified.


Subject(s)
Aromatase Inhibitors/pharmacology , Aromatase/metabolism , Piperidines/pharmacology , Sulfonamides/pharmacology , Aromatase Inhibitors/chemical synthesis , Aromatase Inhibitors/chemistry , Dose-Response Relationship, Drug , Humans , Molecular Structure , Piperidines/chemical synthesis , Piperidines/chemistry , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistry
4.
J Pharm Biomed Anal ; 120: 419-24, 2016 Feb 20.
Article in English | MEDLINE | ID: mdl-26689740

ABSTRACT

Nitric Oxide Synthase (NOS) inhibitors could play a powerful role in inflammatory and neurodegenerative diseases. In this work, novel acetamidine derivatives of NOS were synthesized and the inhibitor activity was evalued. To screen the activity and selectivity, the l-citrulline residue, after the enzymatic NOS assay, was derivatized with o-phthaldialdehyde/N-acetyl cysteine (OPA/NAC) and then evaluated by RP-HPLC method with fluorescence detection. All compounds did not affect the activity of endothelial and neuronal isoforms, while nine of them possessed a percentage of iNOS activity at 10µM lower than 50%, and were selected for IC50 evaluation. Among them, a compound emerged as a very potent (IC50 of 53nM) and selective iNOS inhibitor.


Subject(s)
Amidines/chemical synthesis , Enzyme Inhibitors/analysis , Nitric Oxide Synthase Type II/antagonists & inhibitors , Nitric Oxide Synthase Type II/analysis , Amidines/pharmacokinetics , Chromatography, High Pressure Liquid/methods , Enzyme Activation/drug effects , Enzyme Activation/physiology , Enzyme Inhibitors/pharmacokinetics , Nitric Oxide Synthase Type II/metabolism
5.
ACS Med Chem Lett ; 6(6): 635-40, 2015 Jun 11.
Article in English | MEDLINE | ID: mdl-26101565

ABSTRACT

N-[(3-Aminomethyl)benzyl]acetamidine derivatives were synthesized and in vitro evaluated as inhibitors of the inducible isoform of nitric oxide synthase (iNOS). Because of the high potency of action and the excellent selectivity over the endothelial nitric oxide synthase (eNOS), compound 10 was ex vivo evaluated on isolated and perfused resistance arteries. The results confirm that compound 10 selectively inhibits the iNOS, without affecting the endothelial isoform. The outcome of the docking studies showed that the hydrophobic interaction is the driving force of the binding process, especially for iNOS, where the binding pocket is characterized by a significant lipophilic region.

6.
J Sep Sci ; 37(12): 1380-5, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24687974

ABSTRACT

Nitric oxide synthase (NOS) inhibitors are potential drug candidates due to the critical role of an excessive production of nitric oxide in a range of diseases. At present, the radiometric detection of L-[(3)H]-citrulline produced from L-[(3)H]-arginine during the enzymatic reaction is one of the most accepted methods to assess the in vitro activity of NOS inhibitors. Here we report a fast, easy, and cheap reversed-phase high-performance liquid chromatography method with fluorescence detection, based on the precolumn derivatization of L-citrulline with o-phthaldialdehyde/N-acetyl cysteine, for the in vitro screening of NOS inhibitors. To evaluate enzyme inhibition by the developed method, N-[3-(aminomethyl)benzyl]acetamidine, a potent and selective inhibitor of inducible NOS, was used as a test compound. The half maximal inhibitory concentration obtained was comparable to that derived by the well-established radiometric assay.


Subject(s)
Chromatography, High Pressure Liquid/methods , Chromatography, Reverse-Phase/methods , Enzyme Inhibitors/chemistry , Nitric Oxide Synthase Type II/antagonists & inhibitors , Humans , Kinetics , Nitric Oxide Synthase Type II/chemistry
7.
Med Chem ; 10(1): 59-65, 2014.
Article in English | MEDLINE | ID: mdl-23432317

ABSTRACT

In an effort to develop safe and efficacious compounds for the treatment of metabolic disorders, new compounds based on a combination of clofibric acid, the active metabolite of clofibrate, and trans-stilbene, chalcone, and other lipophilic groups were synthesized. They were evaluated for PPARα transactivation activity; all branched derivatives showed an increase of the transcriptional activity of receptor compared to the linear ones. Noteworthy, stilbene and benzophenone branched derivatives activated the PPARα better than clofibric acid.


Subject(s)
Chalcone/chemistry , Clofibric Acid/pharmacology , PPAR alpha/agonists , Stilbenes/chemistry , Cell Line , Chalcone/pharmacology , Clofibric Acid/chemistry , Humans , Molecular Structure , Stilbenes/pharmacology , Structure-Activity Relationship , Transcriptional Activation/drug effects
8.
Eur J Med Chem ; 58: 317-22, 2012 Dec.
Article in English | MEDLINE | ID: mdl-23137448

ABSTRACT

The identification of novel PPAR ligands represents an attractive research to fully understand the complex biological pathways regulated by these receptors. Selective PPAR modulators, inverse agonists and antagonists of three PPAR isoforms could help to clarify biological effects on lipid and glucose homeostasis. Here we describe the identification of a group of N-(methylsulfonyl)amides, derived from PPARα agonist carboxylic acids. Transactivation and FRET assay confirmed an antagonist behaviour on PPARα for some of these compounds, with submicromolar IC(50). A preliminary analysis on selectivity α/γ revealed different profiles of inhibition or activation.


Subject(s)
PPAR alpha/antagonists & inhibitors , Sulfonamides/pharmacology , Dose-Response Relationship, Drug , HEK293 Cells , Humans , Molecular Structure , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistry
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