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1.
Neurobiol Dis ; 154: 105365, 2021 07.
Article in English | MEDLINE | ID: mdl-33848635

ABSTRACT

The imbalance between production and clearance of amyloid ß (Aß) peptides and their resulting accumulation in the brain is an early and crucial step in the pathogenesis of Alzheimer's disease (AD). Therefore, Aß is strongly positioned as a promising and extensively validated therapeutic target for AD. Investigational disease-modifying approaches aiming at reducing cerebral Aß concentrations include prevention of de novo production of Aß through inhibition of ß-site amyloid precursor protein cleaving enzyme 1 (BACE1), and clearance of Aß deposits via passive Aß immunotherapy. We have developed a novel, high affinity antibody against Aß peptides bearing a pyroglutamate residue at amino acid position 3 (3pE), an Aß species abundantly present in plaque deposits in AD brains. Here, we describe the preclinical characterization of this antibody, and demonstrate a significant reduction in amyloid burden in the absence of microhemorrhages in different mouse models with established plaque deposition. Moreover, we combined antibody treatment with chronic BACE1 inhibitor treatment and demonstrate significant clearance of pre-existing amyloid deposits in transgenic mouse brain, without induction of microhemorrhages and other histopathological findings. Together, these data confirm significant potential for the 3pE-specific antibody to be developed as a passive immunotherapy approach that balances efficacy and safety. Moreover, our studies suggest further enhanced treatment efficacy and favorable safety after combination of the 3pE-specific antibody with BACE1 inhibitor treatment.


Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Amyloid beta-Peptides/antagonists & inhibitors , Antibodies, Monoclonal/administration & dosage , Aspartic Acid Endopeptidases/antagonists & inhibitors , Immunization, Passive/methods , Peptide Fragments/antagonists & inhibitors , Plaque, Amyloid/drug therapy , Amyloid Precursor Protein Secretases/immunology , Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Peptides/immunology , Amyloid beta-Peptides/metabolism , Animals , Antibodies, Monoclonal/immunology , Aspartic Acid Endopeptidases/immunology , Aspartic Acid Endopeptidases/metabolism , Female , Humans , Mice , Mice, Inbred BALB C , Mice, Transgenic , Peptide Fragments/immunology , Peptide Fragments/metabolism , Plaque, Amyloid/immunology , Plaque, Amyloid/metabolism , Treatment Outcome
2.
Sci Rep ; 9(1): 16363, 2019 11 08.
Article in English | MEDLINE | ID: mdl-31705038

ABSTRACT

Multiple animal models have been created to gain insight into Alzheimer's disease (AD) pathology. Among the most commonly used models are transgenic mice overexpressing human amyloid precursor protein (APP) with mutations linked to familial AD, resulting in the formation of amyloid ß plaques, one of the pathological hallmarks observed in AD patients. However, recent evidence suggests that the overexpression of APP by itself can confound some of the reported observations. Therefore, we investigated in the present study the AppNL-G-Fmodel, an App knock-in (App-KI) mouse model that develops amyloidosis in the absence of APP-overexpression. Our findings at the behavioral, electrophysiological, and histopathological level confirmed an age-dependent increase in Aß1-42 levels and plaque deposition in these mice in accordance with previous reports. This had apparently no consequences on cognitive performance in a visual discrimination (VD) task, which was largely unaffected in AppNL-G-F mice at the ages tested. Additionally, we investigated neurophysiological functioning of several brain areas by phase-amplitude coupling (PAC) analysis, a measure associated with adequate cognitive functioning, during the VD task (starting at 4.5 months) and the exploration of home environment (at 5 and 8 months of age). While we did not detect age-dependent changes in PAC during home environment exploration for both the wild-type and the AppNL-G-F mice, we did observe subtle changes in PAC in the wild-type mice that were not present in the AppNL-G-F mice.


Subject(s)
Alzheimer Disease/physiopathology , Amyloid beta-Protein Precursor/genetics , Brain Waves/physiology , Cognition/physiology , Disease Models, Animal , Neurons/pathology , Plaque, Amyloid/pathology , Animals , Behavior, Animal , Discrimination Learning , Gene Knock-In Techniques , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Mutation , Neurons/metabolism , Plaque, Amyloid/metabolism , Visual Perception
3.
Bioorg Med Chem Lett ; 18(21): 5819-23, 2008 Nov 01.
Article in English | MEDLINE | ID: mdl-18922694

ABSTRACT

The synthesis and evaluation of benzetimide derivatives showing potent CXCR3 antagonism are described. Optimization of the screening hits led to the identification of more potent CXCR3 antagonists devoid of anti-cholinergic activity and identification of the key pharmacophore moieties of the series.


Subject(s)
Dexetimide/pharmacology , Receptors, CXCR3/antagonists & inhibitors , Dexetimide/chemistry , Humans , Structure-Activity Relationship
4.
Fetal Diagn Ther ; 24(2): 81-5, 2008.
Article in English | MEDLINE | ID: mdl-18648203

ABSTRACT

OBJECTIVES: If fetal ECG (fECG) devices could be miniaturized sufficiently, one could consider their implantation at the time of fetal surgery to allow permanent monitoring of the fetus and timely intervention in the viable period. We set up an experiment to evaluate the feasibility of in utero direct fECG monitoring and telemetric transmission using a small implantable device in a lamb model. METHODS: A 2-lead miniature ECG sensor (volume 1.9 cm(3); weight 3.9 g) was subcutaneously implanted in 2 fetal lambs at 122 days gestation (range 119-125; term 145 days). The ECG sensor can continuously register and transmit fECG. The signal is captured by an external receiving antenna taped to the maternal abdominal wall. We developed dedicated software running on a commercial laptop for on-line analysis of the transmitted fECG signal. This was a noninterventional study, i.e. daily readings of the fECG signal were done without clinical consequences to the observations. RESULTS: fECG could be successfully registered, transmitted by telemetry and analyzed from the moment of implantation till term birth in one case (24 days). In the second case, unexplained in utero fetal death occurred 12 days after implantation. In this subject, agonal fECG changes were recorded. CONCLUSION: An implanted miniature (<2 ml) ECG sensor can be used to retrieve, process and transmit continuously a qualitative fECG signal in third-trimester fetal lambs. The telemetric signal could be picked up by an external antenna located within a 20-cm range. In this experiment, this was achieved through taping the external receiver to the maternal abdomen. Any acquired signal could be transmitted to a commercially available laptop that could perform on-line analysis of the signal.


Subject(s)
Electrocardiography , Fetal Monitoring/methods , Fetus/surgery , Heart Rate, Fetal , Telemetry , Animals , Electrocardiography/instrumentation , Equipment Design , Feasibility Studies , Female , Fetal Monitoring/instrumentation , Gestational Age , Miniaturization , Pregnancy , Sheep , Signal Processing, Computer-Assisted , Software , Telemetry/instrumentation
5.
J Pharmacol Exp Ther ; 327(1): 1-9, 2008 Oct.
Article in English | MEDLINE | ID: mdl-18599682

ABSTRACT

The interaction between CC chemokine receptor 2 (CCR2) with monocyte chemoattractant proteins, such as MCP-1, regulates the activation and recruitment of inflammatory leukocytes. In this study, we characterized (S)-3-[3,4-difluoro-phenyl)-propyl]-5-isoxazol-5-yl-2-thioxo-2,3-dihydro-1H-imidazole-4-carboxyl acid methyl ester (JNJ-27141491) as a noncompetitive and orally active functional antagonist of human (h)CCR2. JNJ-27141491 strongly suppressed hCCR2-mediated in vitro functions, such as MCP-1-induced guanosine 5'-O-(3-[(35)S]thio)triphosphate binding; MCP-1, -3, and -4-induced Ca(2+) mobilization; and leukocyte chemotaxis toward MCP-1 (IC(50) = 7-97 nM), whereas it had little or no effect on the function of other chemokine receptors tested. The inhibition of CCR2 function was both insurmountable and reversible, consistent with a noncompetitive mode of action. JNJ-27141491 blocked the binding of (125)I-MCP-1 to human monocytes (IC(50) = 0.4 microM), but it failed to affect MCP-1 binding to mouse, rat, and dog cells (IC(50) > 10 microM). Therefore, transgenic mice, in which the mouse (m)CCR2 gene was replaced by the human counterpart, were generated for in vivo testing. In these mice, oral administration of JNJ-27141491 dose-dependently [5-40 mg/kg q.d. (once daily) or b.i.d.] inhibited monocyte and neutrophil recruitment to the alveolar space 48 h after intratracheal mMCP-1/lipopolysaccharide instillation. Furthermore, treatment with JNJ-27141491 (20 mg/kg q.d.) significantly delayed the onset and temporarily reduced neurological signs in an experimental autoimmune encephalomyelitis model of multiple sclerosis. Taken together, these results identify JNJ-27141491 as a noncompetitive, functional antagonist of hCCR2, capable of exerting oral anti-inflammatory activity in transgenic hCCR2-expressing mice.


Subject(s)
Imidazoles/pharmacology , Receptors, CCR2/antagonists & inhibitors , Administration, Oral , Amino Acid Sequence , Animals , CHO Cells , Calcium/metabolism , Cell Movement/drug effects , Chemokine CCL2/metabolism , Chemokine CCL2/pharmacology , Cricetinae , Cricetulus , Dogs , Dose-Response Relationship, Drug , Encephalomyelitis, Autoimmune, Experimental/prevention & control , Humans , Mice , Mice, Inbred C57BL , Mice, Knockout , Molecular Sequence Data , Rats , Rats, Inbred Lew , Receptors, CCR2/metabolism
6.
ChemMedChem ; 3(4): 660-9, 2008 Apr.
Article in English | MEDLINE | ID: mdl-18188859

ABSTRACT

We recently reported the discovery of a series of 2-thioimidazoles as CCR2 antagonists. The most potent molecules of this series, the 4,5-diesters, were rapidly hydrolyzed to the inactive acids and were found to be metabolically unstable. Herein we describe the synthesis of a number of analogues with heterocyclic bioisosteric replacements of the ester group(s). Small 5-membered heterocyclic substituents at the 4-position gave highly potent CCR2 antagonists. Hydrolysis of the 5-ester is diminished, thus imparting these compounds with sufficient stability and systemic exposure after oral administration to warrant further study of the in vivo pharmacology of these functional CCR2 inhibitors.


Subject(s)
Imidazoles/chemical synthesis , Receptors, CCR2/antagonists & inhibitors , Administration, Oral , Animals , Biological Availability , Calcium/metabolism , Cell Line , Chemokine CCL2/antagonists & inhibitors , Drug Stability , Humans , Imidazoles/pharmacokinetics , Imidazoles/pharmacology , Male , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship
7.
Bioorg Med Chem Lett ; 15(3): 497-500, 2005 Feb 01.
Article in English | MEDLINE | ID: mdl-15729771

ABSTRACT

We describe the synthesis and SAR of a new class of CCR2 antagonists based on 2-mercaptoimidazole scaffold. The initial lead 1a was optimized to the 3,4-disubstituted analogues 1p-(S) and 1q-(S), which have IC(50) values in the MCP-1 induced Ca-flux below 0.01 microM.


Subject(s)
Ethylenethiourea/analogs & derivatives , Ethylenethiourea/chemical synthesis , Ethylenethiourea/pharmacology , Receptors, Chemokine/antagonists & inhibitors , Calcium Signaling/drug effects , Cell Line , Chemokine CCL2/pharmacology , Humans , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Inhibitory Concentration 50 , Receptors, CCR2 , Structure-Activity Relationship
8.
J Clin Invest ; 109(3): 327-36, 2002 Feb.
Article in English | MEDLINE | ID: mdl-11827992

ABSTRACT

The murine VEGF gene is alternatively transcribed to yield the VEGF(120), VEGF(164), and VEGF(188) isoforms, which differ in their potential to bind to heparan sulfate and neuropilin-1 and to stimulate endothelial growth. Here, their role in retinal vascular development was studied in mice selectively expressing single isoforms. VEGF(164/164) mice were normal, healthy, and had normal retinal angiogenesis. In contrast, VEGF(120/120) mice exhibited severe defects in vascular outgrowth and patterning, whereas VEGF(188/188) mice displayed normal venular outgrowth but impaired arterial development. It is noteworthy that neuropilin-1, a receptor for VEGF(164), was predominantly expressed in retinal arterioles. These findings reveal distinct roles of the various VEGF isoforms in vascular patterning and arterial development in the retina.


Subject(s)
Endothelial Growth Factors/genetics , Endothelial Growth Factors/physiology , Lymphokines/genetics , Lymphokines/physiology , Retinal Vessels/growth & development , Animals , Arterioles/abnormalities , Arterioles/growth & development , Base Sequence , Body Patterning/genetics , Body Patterning/physiology , DNA/genetics , Female , Gene Expression Regulation, Developmental , Gene Targeting , Male , Mice , Mice, Transgenic , Pregnancy , Protein Isoforms/genetics , Protein Isoforms/physiology , Receptor Protein-Tyrosine Kinases/genetics , Receptors, Growth Factor/genetics , Receptors, Vascular Endothelial Growth Factor , Retinal Vessels/abnormalities , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth Factors , Venules/abnormalities , Venules/growth & development
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