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1.
Eur J Pharm Sci ; 136: 104945, 2019 Aug 01.
Article in English | MEDLINE | ID: mdl-31163216

ABSTRACT

The main challenge of topically applied drugs is to overcome the skin barrier to reach the site of action at the concentration needed for efficacy. In the research of new topical drugs, design of molecules with optimized properties for skin penetration is a key factor and assays for its characterization are needed. A group of 20 representative topical molecules of clinical use were studied in two in silico models (Potts & Guy and Barratt), and an in vitro assay with artificial membrane (Skin-PAMPA). A subset of 9 drugs were also evaluated in the Franz cells assay, formulated in a solvent and in a marketed formulation. Each assay allowed us to grade compounds according to their permeability value. Globally good alignments were found for the studied compounds when comparing models, although discrepancies for some compounds such as tazarotene, tacrolimus, ketoconazole and metronidazole were observed. Overall, the studied in silico and the in vitro models are useful tools to support selection and characterization of research compounds in terms of skin permeability.


Subject(s)
Pharmaceutical Preparations/metabolism , Skin/metabolism , Administration, Cutaneous , Computer Simulation , Humans , Membranes, Artificial , Models, Biological , Permeability , Skin Absorption/drug effects
2.
Eur J Med Chem ; 113: 102-33, 2016 May 04.
Article in English | MEDLINE | ID: mdl-26922232

ABSTRACT

Monocyclic and bicyclic ring systems were investigated as the "core" section of a series of diphenylsulphone-containing acetic acid CRTh2 receptor antagonists. A range of potencies were observed and single-digit nanomolar potencies were obtained in both the monocyclic and bicyclic cores. Residence times for the monocyclic compounds were very short. Some of the bicyclic cores displayed better residence times. A methyl group in the northern part of the core, between the head and tail was a necessary requirement for the beginnings of long residence times. Variations of the tail substitution maximised potencies and residence times.


Subject(s)
Receptors, Immunologic/antagonists & inhibitors , Receptors, Prostaglandin/antagonists & inhibitors , Sulfones/chemistry , Sulfones/pharmacology , Dose-Response Relationship, Drug , Humans , Kinetics , Molecular Structure , Structure-Activity Relationship , Sulfones/chemical synthesis
3.
Pharmacol Res ; 99: 116-24, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26051661

ABSTRACT

Spleen tyrosine kinase (Syk) is essential for signal transduction of immunoreceptors. Inhibition of Syk abrogates mast cell degranulation and B cell responses. We hypothesized that Syk inhibition in the lung by inhaled route could block airway mast cells degranulation and the early asthmatic response without the need of systemic exposure. We discovered LAS189386, a novel Syk inhibitor with suitable properties for inhaled administration. The aim of this study was to characterize the in vitro and in vivo profile of LAS189386. The compound was profiled in Syk enzymatic assay, against a panel of selected kinases and in Syk-dependent cellular assays in mast cells and B cells. Pharmacokinetics and in vivo efficacy was assessed by intratracheal route. Airway resistance and mast cell degranulation after OVA challenge was evaluated in an ovalbumin-sensitized Brown Norway rat model. LAS189386 potently inhibits Syk enzymatic activity (IC50 7.2 nM), Syk phosphorylation (IC50 41 nM), LAD2 cells degranulation (IC50 56 nM), and B cell activation (IC50 22 nM). LAS189386 inhibits early asthmatic response and airway mast cell degranulation without affecting systemic mast cells. The present results support the hypothesis that topical inhibition of Syk in the lung, without systemic exposure, is sufficient to inhibit EAR in rats. Syk inhibition by inhaled route constitutes a promising therapeutic option for asthma.


Subject(s)
Asthma/prevention & control , Azabicyclo Compounds/administration & dosage , Indazoles/administration & dosage , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Mast Cells/drug effects , Protein Kinase Inhibitors/administration & dosage , Protein-Tyrosine Kinases/antagonists & inhibitors , Administration, Inhalation , Animals , Asthma/pathology , Asthma/physiopathology , Azabicyclo Compounds/pharmacokinetics , B-Lymphocytes/drug effects , B-Lymphocytes/physiology , Cell Degranulation/drug effects , Cell Line , Disease Models, Animal , Humans , Indazoles/pharmacokinetics , Male , Mast Cells/physiology , Protein Kinase Inhibitors/pharmacokinetics , Rats , Rats, Inbred BN , Rats, Wistar , Syk Kinase
4.
Bioorg Med Chem Lett ; 25(6): 1217-22, 2015 Mar 15.
Article in English | MEDLINE | ID: mdl-25690784

ABSTRACT

Synthesis and SAR of a series of 7-azaindoles as Orai channel inhibitors showing good potency inhibiting IL-2 production in Jurkat cells is described. Compound 14d displaying best pharmacokinetic properties was further characterized in a model of allergen induced asthma showing inhibition in the number of eosinophils in BALF. High lipophilicity remains as one of the main challenges for this class of compounds.


Subject(s)
Calcium Channel Blockers/chemistry , Calcium Channels/chemistry , Indoles/chemistry , Pyridines/chemistry , Pyrroles/chemistry , Animals , Asthma , Aza Compounds/chemistry , Calcium Channel Blockers/pharmacokinetics , Calcium Channel Blockers/therapeutic use , Calcium Channels/metabolism , Disease Models, Animal , Drug Evaluation, Preclinical , Half-Life , Humans , Hypersensitivity/drug therapy , Hypersensitivity/immunology , Indoles/pharmacokinetics , Indoles/therapeutic use , Interleukin-2/blood , Interleukin-2/metabolism , Jurkat Cells , Microsomes/metabolism , Models, Biological , Ovalbumin/immunology , Protein Binding , Pyridines/pharmacokinetics , Pyridines/therapeutic use , Pyrroles/pharmacokinetics , Pyrroles/therapeutic use , Rats , Structure-Activity Relationship
6.
Bioorg Med Chem Lett ; 24(21): 5123-6, 2014 Nov 01.
Article in English | MEDLINE | ID: mdl-25437505

ABSTRACT

Extensive structure-activity relationship (SAR) and structure-kinetic relationship (SKR) studies in the bicyclic heteroaromatic series of CRTh2 antagonists led to the identification of several molecules that possessed both excellent binding and cellular potencies along with long receptor residence times. A small substituent in the bicyclic core provided an order of magnitude jump in dissociation half-lives. Selected optimized compounds demonstrated suitable pharmacokinetic profiles.


Subject(s)
Acetates/chemistry , Bridged Bicyclo Compounds/chemistry , Receptors, Immunologic/antagonists & inhibitors , Receptors, Prostaglandin/antagonists & inhibitors , Acetates/chemical synthesis , Acetates/pharmacokinetics , Animals , Half-Life , Humans , Indoles/chemistry , Injections, Intravenous , Rats , Rats, Wistar , Receptors, Immunologic/metabolism , Receptors, Prostaglandin/metabolism , Structure-Activity Relationship
8.
ACS Chem Biol ; 9(11): 2678-85, 2014 Nov 21.
Article in English | MEDLINE | ID: mdl-25265274

ABSTRACT

The aggregation of the amyloid-ß peptide (Aß) to form fibrils and plaques is strongly associated with Alzheimer's disease (AD). Although it is well established that this process generates neurotoxicity, it is also heterogeneous with a variety of species being formed during the conversion process. This heterogeneity makes it difficult to detect and characterize each of the aggregates formed, which precludes establishing the specific features responsible for the neurotoxicity observed. Here we use pulse-labeling hydrogen-deuterium exchange experiments analyzed by electrospray ionization mass spectrometry (PL-HDX-ESI-MS) to distinguish three ensembles populated during the aggregation of the 40 and 42 residue forms of the Aß peptide, Aß40 and Aß42, on the basis of differences in their persistent structure. Noticeably, two of them are more abundant at the beginning and at the end of the lag phase and are therefore not detectable by conventional assays such as Thioflavin T (ThT). The ensembles populated at different stages of the aggregation process have a surprisingly consistent average degree of exchange, indicating that there are definite structural transitions between the different stages of aggregation. To determine whether an ensemble of species with a given hydrogen exchange pattern correlates with neurotoxicity, we combined PL-HDX-ESI-MS experiments with parallel measurements of the neurotoxicity of the samples under study. The results of this dual approach show that the maximum toxicity correlates with the ensemble comprising HDX protected oligomers, indicating that development of persistent structure within Aß oligomers is a determinant of neurotoxicity.


Subject(s)
Amyloid beta-Peptides/metabolism , Biopolymers/chemistry , Cell Death , Neurons/cytology , Deuterium , Hydrogen , Spectrometry, Mass, Electrospray Ionization
9.
Nat Commun ; 5: 3443, 2014 Mar 06.
Article in English | MEDLINE | ID: mdl-24599114

ABSTRACT

Reelin is an extracellular matrix protein that is crucial for neural development and adult brain plasticity. While the Reelin signalling cascade has been reported to be associated with Alzheimer's disease (AD), the role of Reelin in this pathology is not understood. Here we use an in vitro approach to show that Reelin interacts with amyloid-ß (Aß42) soluble species, delays Aß42 fibril formation and is recruited into amyloid fibrils. Furthermore, Reelin protects against both the neuronal death and dendritic spine loss induced by Aß42 oligomers. In mice carrying the APP(Swe/Ind) mutation (J20 mice), Reelin overexpression delays amyloid plaque formation and rescues the recognition memory deficits. Our results indicate that by interacting with Aß42 soluble species, delaying Aß plaque formation, protecting against neuronal death and dendritic spine loss and preventing AD cognitive deficits, the Reelin pathway deserves consideration as a therapeutic target for the treatment of AD pathogenesis.


Subject(s)
Amyloid beta-Peptides/metabolism , Amyloid/metabolism , Cell Adhesion Molecules, Neuronal/metabolism , Extracellular Matrix Proteins/metabolism , Nerve Tissue Proteins/metabolism , Serine Endopeptidases/metabolism , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Alzheimer Disease/physiopathology , Amyloid/ultrastructure , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/metabolism , Animals , Behavior, Animal/physiology , Blotting, Western , Brain/metabolism , Brain/pathology , Cell Adhesion Molecules, Neuronal/genetics , Cells, Cultured , Cognition Disorders/genetics , Cognition Disorders/metabolism , Cognition Disorders/physiopathology , Dendritic Spines/metabolism , Disease Models, Animal , Extracellular Matrix Proteins/genetics , HEK293 Cells , Humans , Male , Mice , Mice, Transgenic , Microscopy, Electron, Transmission , Nerve Tissue Proteins/genetics , Peptide Fragments/metabolism , Plaque, Amyloid/metabolism , Protein Binding , Reelin Protein , Serine Endopeptidases/genetics
10.
Bioorg Med Chem Lett ; 22(17): 5419-23, 2012 Sep 01.
Article in English | MEDLINE | ID: mdl-22877633

ABSTRACT

A novel class of potent Syk inhibitors has been developed from rational design. Highly potent aminopyridine derivatives bearing a 4-trifluoromethyl-2-pyridyl motif and represented by compound 13b IC(50): 0.6 nM were identified. Substitution by a 2-pyrazinyl motif and SAR expansion in position 4 of the central core provided diverse potent non-cytotoxic Syk inhibitors showing nanomolar activity inhibiting human mast cell line LAD2 degranulation.


Subject(s)
Aminopyridines/chemistry , Aminopyridines/pharmacology , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Mast Cells/drug effects , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Binding Sites , Cell Degranulation/drug effects , Cell Line , Humans , Intracellular Signaling Peptides and Proteins/chemistry , Intracellular Signaling Peptides and Proteins/metabolism , Mast Cells/enzymology , Mast Cells/physiology , Molecular Docking Simulation , Protein-Tyrosine Kinases/chemistry , Protein-Tyrosine Kinases/metabolism , Syk Kinase
11.
Bioorg Med Chem Lett ; 22(10): 3431-6, 2012 May 15.
Article in English | MEDLINE | ID: mdl-22521646

ABSTRACT

A new class of p38α inhibitors based on a biaryl-triazolopyridine scaffold was investigated. X-ray crystallographic data of the initial lead compound cocrystallised with p38α was crucial in order to uncover a unique binding mode of the inhibitor to the hinge region via a pair of water molecules. Synthesis and SAR was directed towards the improvement of binding affinity, as well as ADME properties for this new class of p38α inhibitors and ultimately afforded compounds showing good in vivo efficacy.


Subject(s)
Benzamides/pharmacology , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Crystallography, X-Ray , Models, Molecular , Structure-Activity Relationship
12.
Bioorg Med Chem Lett ; 22(8): 2784-8, 2012 Apr 15.
Article in English | MEDLINE | ID: mdl-22425453

ABSTRACT

A series of aminopyrazines as inhibitors of Syk kinase activity and showing inhibition of LAD2 cells degranulation is described. Optimization of the carboxamide motif with aminomethylpiperidines provided high potency inhibiting Syk but low cellular activity. Amides of cis and trans adamantanol showed good inhibitory activity against Syk as well as remarkable activity in LAD2 cells degranulation assay.


Subject(s)
Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrazines/chemical synthesis , Pyrazines/pharmacology , Adamantane/analogs & derivatives , Adamantane/chemistry , Adamantane/pharmacology , Cell Line, Tumor , Crystallography, X-Ray , Enzyme Activation/drug effects , Enzyme Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , Molecular Structure , Pyrazines/chemistry , Syk Kinase
13.
J Med Chem ; 54(22): 7899-910, 2011 Nov 24.
Article in English | MEDLINE | ID: mdl-21999461

ABSTRACT

The design, synthesis, and ability to inhibit p38α MAP kinase by a novel series of naphthyridine N-oxides will be described. Some of these compounds showed a significant reduction in the LPS-induced TNFα production in human whole blood. Structure-activity relationship studies revealed that N-oxide oxygen was essential for activity and was probably a determinant factor for its marked selectivity against other related kinases. After an extensive SAR exercise, several compounds from this series were identified as very potent p38α inhibitors. In vivo efficacy of some derivatives was demonstrated to reduce TNFα levels in an acute murine model of inflammation (ED(50) = 0.5 mg/kg in LPS-induced TNFα production when dosed orally 1.5 h prior to LPS administration). The oral efficacy was further demonstrated in a chronic model of adjuvant arthritis in rats with established disease when administered orally (ED(50) < 1 mg/kg).


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Naphthyridines/chemical synthesis , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Arthritis, Experimental/drug therapy , Binding Sites , Cell Line , Crystallography, X-Ray , Humans , Inflammation/drug therapy , Inflammation/etiology , Lipopolysaccharides/pharmacology , Male , Mice , Microsomes, Liver/metabolism , Monocytes/drug effects , Monocytes/metabolism , Naphthyridines/pharmacokinetics , Naphthyridines/pharmacology , Protein Binding , Protein Conformation , Rats , Rats, Wistar , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/biosynthesis
15.
ACS Med Chem Lett ; 2(3): 213-8, 2011 Mar 10.
Article in English | MEDLINE | ID: mdl-24900298

ABSTRACT

The structure-activity relationships for a series of pyrazine-based A2B adenosine receptor antagonists are described. From this work, LAS101057 (17), a potent, selective, and orally efficacious A2B receptor antagonist, was identified as a clinical development candidate. LAS101057 inhibits agonist-induced IL-6 production in human fibroblasts and is active in an ovalbumin (OVA)-sensitized mouse model after oral administration, reducing airway hyperresponsiveness to methacholine, Th2 cytokine production, and OVA-specific IgE levels.

16.
Eur J Med Chem ; 45(7): 2884-92, 2010 Jul.
Article in English | MEDLINE | ID: mdl-20371139

ABSTRACT

A new series of 9-deazaxanthine derivatives with various substituents at the heterocyclic system were synthesized and evaluated for their binding affinities for the four human recombinant adenosine receptors, A(1)-A(3) subtypes. A number of the 9-deazaxanthines derivatives 3a-m showed moderate-to-high affinity for hA(2B) receptors, with compound 3f showing a 32-fold selectivity for A(2B) over A(1) and a 2750-fold selectivity for A(2B) over A(2A).


Subject(s)
Adenosine A2 Receptor Antagonists , Xanthines/chemical synthesis , Xanthines/pharmacology , Animals , CHO Cells , Cricetinae , Cricetulus , HeLa Cells , Humans , Ligands , Xanthines/chemistry
17.
Bioorg Med Chem Lett ; 20(5): 1634-7, 2010 Mar 01.
Article in English | MEDLINE | ID: mdl-20138516

ABSTRACT

Several new potent and selective A(2B) adenosine receptor antagonists have been prepared in which the aryl-amide moiety of the lead series, exemplified by 1a, has been replaced by bioisosteric bicyclic moieties. Although the majority of compounds had generally improved microsomal stability as compared to 1a, this was not translated into overall improvements in the pharmacokinetic profiles of a representative set of compounds.


Subject(s)
Adenosine A2 Receptor Antagonists , Amides/chemistry , Anti-Inflammatory Agents/chemistry , Bridged Bicyclo Compounds/chemistry , Animals , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/pharmacokinetics , Bridged Bicyclo Compounds/chemical synthesis , Bridged Bicyclo Compounds/pharmacokinetics , Drug Discovery , Humans , Microsomes, Liver/metabolism , NADP/metabolism , Rats , Receptor, Adenosine A2B/metabolism
19.
J Med Chem ; 52(17): 5531-45, 2009 Sep 10.
Article in English | MEDLINE | ID: mdl-19678708

ABSTRACT

A novel series of aminopyridine N-oxides were designed, synthesized, and tested for their ability to inhibit p38alpha MAP kinase. Some of these compounds showed a significant reduction in the LPS-induced TNFalpha production in human whole blood. Structure-activity relationship studies revealed that N-oxide oxygen was essential for activity and was probably a determinant factor for a marked selectivity against other related kinases. Compound 45 was identified as a potent and selective p38alpha inhibitor with an appropriate balance between potency and pharmacokinetics. In vivo efficacy of 45 was demonstrated in reducing TNFalpha levels in an acute murine model of inflammation (ED(50) = 1 mg/kg in LPS-induced TNFalpha production when dosed orally 1.5 h prior to LPS administration). The oral efficacy of 45 was further demonstrated in a chronic model of adjuvant arthritis in rats with established disease when administered orally (ED(50) = 4.5 mg/kg).


Subject(s)
Aminopyridines/chemistry , Aminopyridines/pharmacology , Drug Design , Oxides/chemistry , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Aminopyridines/chemical synthesis , Aminopyridines/therapeutic use , Animals , Arthritis, Experimental/blood , Arthritis, Experimental/drug therapy , Catalytic Domain , Cell Line , Humans , Inhibitory Concentration 50 , Male , Models, Molecular , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/therapeutic use , Rats , Rats, Wistar , Structure-Activity Relationship , Substrate Specificity , Tumor Necrosis Factor-alpha/biosynthesis , Tumor Necrosis Factor-alpha/blood , p38 Mitogen-Activated Protein Kinases/chemistry
20.
Bioorg Med Chem ; 17(10): 3618-29, 2009 May 15.
Article in English | MEDLINE | ID: mdl-19398343

ABSTRACT

A number of 1,3-dialkyl-9-deazaxanthines (9-dAXs), bearing a variety of N-substituted benzyloxycarbonylamino substituents at position 8, were prepared and evaluated for their binding affinity to the recombinant human adenosine receptors (hARs), chiefly to the hA(2B) and hA(2A) AR subtypes. Several ligands endowed with excellent binding affinity to the hA(2B) receptors, but low selectivity versus hA(2A) and hA(1) were identified. Among these, 1,3-dimethyl-N-3'-thienyl carbamate 15 resulted as the most potent ligand at hA(2B) (K(i)=0.8 nM), with a low selectivity versus hA(2A) (hA(2A)/hA(2B)=12.6) and hA(1) (hA(1)/hA(2B)=12.5) and a higher selectivity versus hA(3) (hA(3)/hA(2B)=454). When tested in functional assays in vitro, compound 15 exhibited high antagonist activities and efficacies versus both the A(2A) and A(2B) receptor subtypes, with pA(2) values close to the corresponding pK(i)s. A comparative analysis of structure-affinity and structure-selectivity relationships of the similar analogues 8-N-substituted benzyloxycarbonylamino- and 8-N-substituted phenoxyacetamido-9-dAXs suggested that their binding modes at the hA(2B) and hA(2A) ARs may strongly differ. Computational studies help to clarify this striking difference arising from a simple, albeit crucial, structural change, from CH(2)OCON to OCH(2)CON, in the para-position of the 8-phenyl ring.


Subject(s)
Carbamates/chemistry , Purinergic P1 Receptor Antagonists , Xanthines/chemistry , Adenosine A1 Receptor Antagonists , Adenosine A2 Receptor Antagonists , Adenosine A3 Receptor Antagonists , Animals , Carbamates/chemical synthesis , Carbamates/pharmacology , Cell Line , Drug Design , Humans , Male , Models, Chemical , Rats , Rats, Wistar , Receptor, Adenosine A1/metabolism , Receptor, Adenosine A2A/metabolism , Receptor, Adenosine A2B/metabolism , Receptor, Adenosine A3/metabolism , Receptors, Purinergic P1/metabolism , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/metabolism , Xanthines/chemical synthesis , Xanthines/pharmacology
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