Publications by authors named "Rosana Leiva"

16 Publications

  • Page 1 of 1

2-Oxaadamant-1-yl Ureas as Soluble Epoxide Hydrolase Inhibitors: Evaluation in a Murine Model of Acute Pancreatitis.

J Med Chem 2020 09 25;63(17):9237-9257. Epub 2020 Aug 25.

Laboratori de Quı́mica Farmacèutica (Unitat Associada al CSIC), Departament de Farmacologia, Toxicologia i Quı́mica Terapèutica, Facultat de Farmàcia i Ciències de l'Alimentació, and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Joan XXIII, 27-31, 08028 Barcelona, Spain.

pharmacological inhibition of soluble epoxide hydrolase (sEH) reduces inflammatory diseases, including acute pancreatitis (AP). Adamantyl ureas are very potent sEH inhibitors, but the lipophilicity and metabolism of the adamantane group compromise their overall usefulness. Herein, we report that the replacement of a methylene unit of the adamantane group by an oxygen atom increases the solubility, permeability, and stability of three series of urea-based sEH inhibitors. Most of these oxa-analogues are nanomolar inhibitors of both the human and murine sEH. Molecular dynamics simulations rationalize the molecular basis for their activity and suggest that the presence of the oxygen atom on the adamantane scaffold results in active site rearrangements to establish a weak hydrogen bond. The 2-oxaadamantane , which has a good solubility, microsomal stability, and selectivity for sEH, was selected for further and studies in models of cerulein-induced AP. Both in prophylactic and treatment studies, diminished the overexpression of inflammatory and endoplasmic reticulum stress markers induced by cerulein and reduced the pancreatic damage.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755424PMC
September 2020

Pharmacological Inhibition of Soluble Epoxide Hydrolase as a New Therapy for Alzheimer's Disease.

Neurotherapeutics 2020 10;17(4):1825-1835

Department of Pharmacy and Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences and Institute of Biomedicine, University of Barcelona, Av. Joan XXIII, 27-31, E-08028, Barcelona, Spain.

The inhibition of the enzyme soluble epoxide hydrolase (sEH) has demonstrated clinical therapeutic effects in several peripheral inflammatory-related diseases, with 3 compounds in clinical trials. However, the role of this enzyme in the neuroinflammation process has been largely neglected. Herein, we disclose the pharmacological validation of sEH as a novel target for the treatment of Alzheimer's disease (AD). Evaluation of cognitive impairment and pathological hallmarks were used in 2 models of age-related cognitive decline and AD using 3 structurally different and potent sEH inhibitors as chemical probes. sEH is upregulated in brains from AD patients. Our findings supported the beneficial effects of central sEH inhibition, regarding reducing cognitive impairment, neuroinflammation, tau hyperphosphorylation pathology, and the number of amyloid plaques. This study suggests that inhibition of inflammation in the brain by targeting sEH is a relevant therapeutic strategy for AD.
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http://dx.doi.org/10.1007/s13311-020-00854-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851240PMC
October 2020

A Novel NMDA Receptor Antagonist Protects against Cognitive Decline Presented by Senescent Mice.

Pharmaceutics 2020 Mar 22;12(3). Epub 2020 Mar 22.

Pharmacology Section, Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institute of Neuroscience, University of Barcelona (NeuroUB), Av. Joan XXIII 27-31, 08028 Barcelona, Spain.

Alzheimer's disease (AD) is the leading cause of dementia. Non-competitive N-Methyl-D-aspartate (NMDA) receptor antagonist memantine improved cognition and molecular alterations after preclinical treatment. Nevertheless, clinical results are discouraging. In vivo efficacy of the RL-208, a new NMDA receptor blocker described recently, with favourable pharmacokinetic properties was evaluated in Senescence accelerated mice prone 8 (SAMP8), a mice model of late-onset AD (LOAD). Oral administration of RL-208 improved cognitive performance assessed by using the three chamber test (TCT), novel object recognition test (NORT), and object location test (OLT). Consistent with behavioural results, RL-208 treated-mice groups significantly changed NMDAR2B phosphorylation state levels but not NMDAR2A. Calpain-1 and Caspase-3 activity was reduced, whereas B-cell lymphoma-2 (BCL-2) levels increased, indicating reduced apoptosis in RL-208 treated SAMP8. Superoxide Dismutase 1 (SOD1) and Glutathione Peroxidase 1 (GPX1), as well as a reduction of hydrogen peroxide (HO), was also determined in RL-208 mice. RL-208 treatment induced an increase in mature brain-derived neurotrophic factor (mBDNF), prevented Tropomyosin-related kinase B full-length (TrkB-FL) cleavage, increased protein levels of Synaptophysin (SYN) and Postsynaptic density protein 95 (PSD95). In whole, these results point out to an improvement in synaptic plasticity. Remarkably, RL-208 also decreased the protein levels of Cyclin-Dependent Kinase 5 (CDK5), as well as p25/p35 ratio, indicating a reduction in kinase activity of CDK5/p25 complex. Consequently, lower levels of hyperphosphorylated Tau (p-Tau) were found. In sum, these results demonstrate the neuroprotectant role of RL-208 through NMDAR blockade.
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http://dx.doi.org/10.3390/pharmaceutics12030284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7151078PMC
March 2020

Exploring the size of the lipophilic unit of the soluble epoxide hydrolase inhibitors.

Bioorg Med Chem 2019 10 26;27(20):115078. Epub 2019 Aug 26.

Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia i Ciències de l'Alimentació, and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Joan XXIII 27-31, Barcelona E-08028, Spain. Electronic address:

Soluble epoxide hydrolase (sEH) inhibitors are potential drugs for several diseases. Adamantyl ureas are excellent sEH inhibitors but have limited metabolic stability. Herein, we report the effect of replacing the adamantane group by alternative polycyclic hydrocarbons on sEH inhibition, solubility, permeability and metabolic stability. Compounds bearing smaller or larger polycyclic hydrocarbons than adamantane yielded all good inhibition potency of the human sEH (0.4 ≤ IC ≤ 21.7 nM), indicating that sEH is able to accommodate inhibitors of very different size. Human liver microsomal stability of diamantane containing inhibitors is lower than that of their corresponding adamantane counterparts.
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http://dx.doi.org/10.1016/j.bmc.2019.115078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6892585PMC
October 2019

11β-HSD1 Inhibition Rescues SAMP8 Cognitive Impairment Induced by Metabolic Stress.

Mol Neurobiol 2020 Jan 9;57(1):551-565. Epub 2019 Aug 9.

Pharmacology Section, Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Av Joan XXIII 27-31, 08028, Barcelona, Spain.

Ageing and obesity have been shown to increase the risk of cognitive decline and Alzheimer's disease (AD). Besides, elevated glucocorticoid (GCs) levels cause metabolic stress and have been associated with the neurodegenerative process. Direct pieces of evidence link the reduction of GCs caused by the inhibition of 11β-HSD type 1 (11β-HSD1) with cognitive improvement. In the present study, we investigated the beneficial effects of 11β-HSD1 inhibitor (i) RL-118 after high-fat diet (HFD) treatment in the senescence-accelerated mouse prone 8 (SAMP8). We found an improvement in glucose intolerance induced by HFD in mice treated with RL-118, a significant reduction in 11β-HSD1 and glucocorticoid receptor (GR) protein levels. Furthermore, specific modifications in the FGF21 activation after treatment with 11β-HSD1i, RL-118, which induced changes in SIRT1/PGC1α/AMPKα pathway, were found. Oxidative stress (OS) and reactive oxygen species (ROS), as well as inflammatory markers and microglial activation, were significantly diminished in HFD mice treated with 11β-HSD1i. Remarkably, treatment with 11β-HSD1i altered PERK pathway in both diet groups, increasing autophagy only in HFD mice group. After RL-118 treatment, a decrease in glycogen synthase kinase 3 (GSK3β) activation, Tau hyperphosphorylation, BACE1 protein levels and the product β-CTF were found. Increases in the non-amyloidogenic secretase ADAM10 protein levels and the product sAPPα were found in both treated mice, regardless of the diet. Consequently, beneficial effects on social behaviour and cognitive performance were found in treated mice. Thus, our results support the therapeutic strategy of selective 11β-HSD1i for the treatment of age-related cognitive decline and AD.
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http://dx.doi.org/10.1007/s12035-019-01708-4DOI Listing
January 2020

Pentafluorosulfanyl-containing Triclocarban Analogs with Potent Antimicrobial Activity.

Molecules 2018 Nov 2;23(11). Epub 2018 Nov 2.

Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia i Ciències de l'Alimentació, and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Joan XXIII, 27-31, 08028 Barcelona, Spain.

Concerns have been raised about the long-term accumulating effects of triclocarban, a polychlorinated diarylurea widely used as an antibacterial soap additive, in the environment and in human beings. Indeed, the Food and Drug Administration has recently banned it from personal care products. Herein, we report the synthesis, antibacterial activity and cytotoxicity of novel ,'-diarylureas as triclocarban analogs, designed by reducing one or more chlorine atoms of the former and/or replacing them by the novel pentafluorosulfanyl group, a new bioisostere of the trifluoromethyl group, with growing importance in drug discovery. Interestingly, some of these pentafluorosulfanyl-bearing ureas exhibited high potency, broad spectrum of antimicrobial activity against Gram-positive bacterial pathogens, and high selectivity index, while displaying a lower spontaneous mutation frequency than triclocarban. Some lines of evidence suggest a bactericidal mode of action for this family of compounds.
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http://dx.doi.org/10.3390/molecules23112853DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278391PMC
November 2018

Pharmacological and Electrophysiological Characterization of Novel NMDA Receptor Antagonists.

ACS Chem Neurosci 2018 11 1;9(11):2722-2730. Epub 2018 Jun 1.

Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia i Ciències de l'Alimentació i Institut de Biomedicina (IBUB) , Universitat de Barcelona , Av. Joan XXIII, 27-31 , 08028 Barcelona , Spain.

This work reports the synthesis and pharmacological and electrophysiological evaluation of new N-methyl-d-aspartic acid receptor (NMDAR) channel blocking antagonists featuring polycyclic scaffolds. Changes in the chemical structure modulate the potency and voltage dependence of inhibition. Two of the new antagonists display properties comparable to those of memantine, a clinically approved NMDAR antagonist.
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http://dx.doi.org/10.1021/acschemneuro.8b00154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6249113PMC
November 2018

11β-HSD1 Inhibition by RL-118 Promotes Autophagy and Correlates with Reduced Oxidative Stress and Inflammation, Enhancing Cognitive Performance in SAMP8 Mouse Model.

Mol Neurobiol 2018 Dec 2;55(12):8904-8915. Epub 2018 Apr 2.

Secció de Farmacologia i Toxicologia and Institut de Neurociències, Facultat de Farmàcia i Ciències de l'Alimentació, Universitat de Barcelona, Av. Joan XXIII, 27-31, 08028, Barcelona, Spain.

Elevated glucocorticoid (GC) exposure is widely accepted as a key factor in the age-related cognitive decline in rodents and humans. 11β-HSD1 is a key enzyme in the GCs pathway, catalyzing the conversion of 11β-dehydrocorticosterone to corticosterone in mice, with possible implications in neurodegenerative processes and cognitive impairment. Here, we determined the effect of a new 11β-HSD1 inhibitor, RL-118, administered to 12-month-old senescence-accelerated mouse-prone 8 (SAMP8) mice with neuropathological AD-like hallmarks and widely used as a rodent model of cognitive dysfunction. Behavioral tests (open field and object location) and neurodegeneration molecular markers were studied. After RL-118 treatment, increased locomotor activity and cognitive performance were found. Likewise, we found changes in hippocampal autophagy markers such as Beclin1, LC3B, AMPKα, and mTOR, indicating a progression in the autophagy process. In line with autophagy increase, a diminution in phosphorylated tau species (Ser 396 and Ser 404) jointly with an increase in ADAM10 and sAPPα indicated that an improvement in removing the abnormal proteins by autophagy might be implicated in the neuroprotective role of the 11β-HSD1 inhibitor. In addition, gene expression of oxidative stress (OS) and inflammatory markers, such as Hmox1, Aldh2, Il-1β, and Ccl3, were reduced in old treated mice in comparison to that of the control group. Consistent with this, we further demonstrate a significant correlation with autophagy markers and cognitive improvement and significant inverse correlation with autophagy, OS, and neuroinflammation markers. We concluded that inhibition of 11β-HSD1 by RL-118 prevented neurodegenerative processes and cognitive decline, acting on autophagy process, being an additional neuroprotective mechanism not described previously.
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http://dx.doi.org/10.1007/s12035-018-1026-8DOI Listing
December 2018

Exploring N-acyl-4-azatetracyclo[5.3.2.0.0]dodec-11-enes as 11β-HSD1 Inhibitors.

Molecules 2018 Feb 28;23(3). Epub 2018 Feb 28.

Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia i Ciències de l'Alimentació, and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Joan XXIII, 27-31, E-08028 Barcelona, Spain.

We recently found that a cyclohexanecarboxamide derived from 4-azatetracyclo[5.3.2.0.0]dodec-11-ene displayed low nanomolar inhibition of 11β-HSD1. In continuation of our efforts to discover potent and selective 11β-HSD1 inhibitors, herein we explored several replacements for the cyclohexane ring. Some derivatives exhibited potent inhibitory activity against human 11β-HSD1, although with low selectivity over the isoenzyme 11β-HSD2, and poor microsomal stability.
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http://dx.doi.org/10.3390/molecules23030536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6017749PMC
February 2018

Aniline-Based Inhibitors of Influenza H1N1 Virus Acting on Hemagglutinin-Mediated Fusion.

J Med Chem 2018 01 22;61(1):98-118. Epub 2017 Dec 22.

Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia i Ciències de l'Alimentació, and Institute of Biomedicine (IBUB), Universitat de Barcelona , Av. Joan XXIII, 27-31, Barcelona E-08028, Spain.

Two series of easily accessible anilines were identified as inhibitors of influenza A virus subtype H1N1, and extensive chemical synthesis and analysis of the structure-activity relationship were performed. The compounds were shown to interfere with low pH-induced membrane fusion mediated by the H1 and H5 (group 1) hemagglutinin (HA) subtypes. A combination of virus resistance, HA interaction, and molecular dynamics simulation studies elucidated the binding site of these aniline-based influenza fusion inhibitors, which significantly overlaps with the pocket occupied by some H3 HA-specific inhibitors, indicating the high relevance of this cavity for drug design.
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http://dx.doi.org/10.1021/acs.jmedchem.7b00908DOI Listing
January 2018

Design, synthesis and in vivo study of novel pyrrolidine-based 11β-HSD1 inhibitors for age-related cognitive dysfunction.

Eur J Med Chem 2017 Oct 4;139:412-428. Epub 2017 Aug 4.

Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia i Cienciès de l'Alimentació, and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Joan XXIII 27-31, Barcelona E-08028, Spain. Electronic address:

Recent findings suggest that treatment with 11β-HSD1 inhibitors provides a novel approach to deal with age-related cognitive dysfunctions, including Alzheimer's disease. In this work we report potent 11β-HSD1 inhibitors featuring unexplored pyrrolidine-based polycyclic substituents. A selected candidate administered to 12-month-old SAMP8 mice for four weeks prevented memory deficits and displayed a neuroprotective action. This is the first time that 11β-HSD1 inhibitors have been studied in this broadly-used mouse model of accelerated senescence and late-onset Alzheimer's disease.
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http://dx.doi.org/10.1016/j.ejmech.2017.08.003DOI Listing
October 2017

Mechanism of the Pseudoirreversible Binding of Amantadine to the M2 Proton Channel.

J Am Chem Soc 2016 11 16;138(47):15345-15358. Epub 2016 Nov 16.

Department of Nutrition, Food Science and Gastronomy, Faculty of Pharmacy and Food Sciences, and Institute of Biomedicine (IBUB), University of Barcelona , Avgda. Prat de la Riba 171, 08921 Santa Coloma de Gramenet, Spain.

The M2 proton channel of influenza A virus is an integral membrane protein involved in the acidification of the viral interior, a step necessary for the release of the viral genetic material and replication of new virions. The aim of this study is to explore the mechanism of drug (un)binding to the M2 channel in order to gain insight into the structural and energetic features relevant for the development of novel inhibitors. To this end, we have investigated the binding of amantadine (Amt) to the wild type (wt) M2 channel and its V27A variant using multiple independent molecular dynamics simulations, exploratory conventional metadynamics, and multiple-walkers well-tempered metadynamics calculations. The results allow us to propose a sequential mechanism for the (un)binding of Amt to the wt M2 channel, which involves the adoption of a transiently populated intermediate (up state) leading to the thermodynamically favored down binding mode in the channel pore. Furthermore, they suggest that chloride anions play a relevant role in stabilizing the down binding mode of Amt to the wt channel, giving rise to a kinetic trapping that explains the experimentally observed pseudoirreversible inhibition of the wt channel by Amt. We propose that this trapping mechanism underlies the inhibitory activity of potent M2 channel blockers, as supported by the experimental confirmation of the irreversible binding of a pyrrolidine analogue from electrophysiological current assays. Finally, the results reveal that the thermodynamics and kinetics of Amt (un)binding is very sensitive to the V27A mutation, providing a quantitative rationale to the drastic decrease in inhibitory potency against the V27A variant. Overall, these findings pave the way to explore the inhibitory activity of Amt-related analogues in mutated M2 channel variants, providing guidelines for the design of novel inhibitors against resistant virus strains.
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http://dx.doi.org/10.1021/jacs.6b07096DOI Listing
November 2016

Heme-Regulated eIF2α Kinase Modulates Hepatic FGF21 and Is Activated by PPARβ/δ Deficiency.

Diabetes 2016 10 2;65(10):3185-99. Epub 2016 Aug 2.

Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Institute of Biomedicine of the University of Barcelona, Barcelona, Spain CIBERDEM, Instituto de Salud Carlos III, Madrid, Spain Pediatric Research Institute, Hospital Sant Joan de Déu, Barcelona, Spain

Fibroblast growth factor 21 (FGF21), a peptide hormone with pleiotropic effects on carbohydrate and lipid metabolism, is considered a target for the treatment of diabetes. We investigated the role of peroxisome proliferator-activated receptor (PPAR) β/δ deficiency in hepatic FGF21 regulation. Increased Fgf21 expression was observed in the livers of PPARβ/δ-null mice and in mouse primary hepatocytes when this receptor was knocked down by small interfering RNA (siRNA). Increased Fgf21 was associated with enhanced protein levels in the heme-regulated eukaryotic translation initiation factor 2α (eIF2α) kinase (HRI). This increase caused enhanced levels of phosphorylated eIF2α and activating transcription factor (ATF) 4, which is essential for Fgf21-induced expression. siRNA analysis demonstrated that HRI regulates Fgf21 expression in primary hepatocytes. Enhanced Fgf21 expression attenuated tunicamycin-induced endoplasmic reticulum stress, as demonstrated by using a neutralizing antibody against FGF21. Of note, increased Fgf21 expression in mice fed a high-fat diet or hepatocytes exposed to palmitate was accompanied by reduced PPARβ/δ and activation of the HRI-eIF2α-ATF4 pathway. Moreover, pharmacological activation of HRI increased Fgf21 expression and reduced lipid-induced hepatic steatosis and glucose intolerance, but these effects were not observed in Fgf21-null mice. Overall, these findings suggest that HRI is a potential target for regulating hepatic FGF21 levels.
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http://dx.doi.org/10.2337/db16-0155DOI Listing
October 2016

Novel 11β-HSD1 inhibitors: C-1 versus C-2 substitution and effect of the introduction of an oxygen atom in the adamantane scaffold.

Bioorg Med Chem Lett 2015 Oct 5;25(19):4250-3. Epub 2015 Aug 5.

Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Joan XXIII, s/n, Barcelona E-08028, Spain. Electronic address:

The adamantane scaffold is found in several marketed drugs and in many investigational 11β-HSD1 inhibitors. Interestingly, all the clinically approved adamantane derivatives are C-1 substituted. We demonstrate that, in a series of paired adamantane isomers, substitution of the adamantane in C-2 is preferred over the substitution at C-1 and is necessary for potency at human 11β-HSD1. Furthermore, the introduction of an oxygen atom in the hydrocarbon scaffold of adamantane is deleterious to 11β-HSD1 inhibition. Molecular modeling studies provide a basis to rationalize these features.
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http://dx.doi.org/10.1016/j.bmcl.2015.07.097DOI Listing
October 2015

Ritter reaction-mediated syntheses of 2-oxaadamantan-5-amine, a novel amantadine analog.

Tetrahedron Lett 2015 Mar 31;56(10):1272-1275. Epub 2015 Jan 31.

Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av. Joan XXIII, s/n, Barcelona E-08028, Spain.

Two alternative syntheses of 2-oxaadamantan-5-amine, a novel analog of the clinically approved drug amantadine, are reported. The compound has been tested as an anti-influenza A virus agent and as an NMDA receptor antagonist. While the compound was not antivirally active, it displayed moderate activity as an NMDA receptor antagonist.
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http://dx.doi.org/10.1016/j.tetlet.2015.01.160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7125674PMC
March 2015

Azapropellanes with anti-influenza a virus activity.

ACS Med Chem Lett 2014 Jul 2;5(7):831-6. Epub 2014 May 2.

Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and Institute of Biomedicine (IBUB), Universitat de Barcelona , Av. Diagonal 643, Barcelona E-08028, Spain.

The synthesis of several [4,4,3], [4,3,3], and [3,3,3]azapropellanes is reported. Several of the novel amines displayed low-micromolar activities against an amantadine-resistant H1N1 strain, but they did not show activity against an amantadine-sensitive H3N2 strain. None of the tested compounds inhibit the influenza A/M2 proton channel function. Most of the compounds did not show cytotoxicity for MDCK cells.
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http://dx.doi.org/10.1021/ml500108sDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4094260PMC
July 2014