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1.
J Med Chem ; 56(8): 3177-90, 2013 Apr 25.
Article in English | MEDLINE | ID: mdl-23516963

ABSTRACT

We have developed two parallel series, A and B, of CX3CR1 antagonists for the treatment of multiple sclerosis. By modifying the substituents on the 7-amino-5-thio-thiazolo[4,5-d]pyrimidine core structure, we were able to achieve compounds with high selectivity for CX3CR1 over the closely related CXCR2 receptor. The structure-activity relationships showed that a leucinol moiety attached to the core-structure in the 7-position together with α-methyl branched benzyl derivatives in the 5-position displayed promising affinity, and selectivity as well as physicochemical properties, as exemplified by compounds 18a and 24h. We show the preparation of the first potent and selective orally available CX3CR1 antagonists.


Subject(s)
Multiple Sclerosis/drug therapy , Pyrimidines/pharmacology , Receptors, Chemokine/antagonists & inhibitors , Thiazoles/pharmacology , Amino Alcohols/chemical synthesis , Amino Alcohols/pharmacokinetics , Amino Alcohols/pharmacology , Animals , CX3C Chemokine Receptor 1 , Caco-2 Cells , Humans , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Pyrimidines/pharmacokinetics , Rats , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/chemistry , Thiazoles/pharmacokinetics
2.
J Neurosci ; 32(48): 17297-305, 2012 Nov 28.
Article in English | MEDLINE | ID: mdl-23197721

ABSTRACT

γ-Secretase inhibition represents a major therapeutic strategy for lowering amyloid ß (Aß) peptide production in Alzheimer's disease (AD). Progress toward clinical use of γ-secretase inhibitors has, however, been hampered due to mechanism-based adverse events, primarily related to impairment of Notch signaling. The γ-secretase inhibitor MRK-560 represents an exception as it is largely tolerable in vivo despite displaying only a small selectivity between Aß production and Notch signaling in vitro. In exploring the molecular basis for the observed tolerability, we show that MRK-560 displays a strong preference for the presenilin 1 (PS1) over PS2 subclass of γ-secretases and is tolerable in wild-type mice but causes dose-dependent Notch-related side effect in PS2-deficient mice at drug exposure levels resulting in a substantial decrease in brain Aß levels. This demonstrates that PS2 plays an important role in mediating essential Notch signaling in several peripheral organs during pharmacological inhibition of PS1 and provide preclinical in vivo proof of concept for PS2-sparing inhibition as a novel, tolerable and efficacious γ-secretase targeting strategy for AD.


Subject(s)
Alzheimer Disease/drug therapy , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Amyloid beta-Peptides/metabolism , Brain/drug effects , Presenilin-2/metabolism , Alzheimer Disease/metabolism , Animals , Brain/metabolism , Mice , Presenilin-2/genetics , Receptors, Notch/genetics , Receptors, Notch/metabolism , Signal Transduction/drug effects , Signal Transduction/physiology , Sulfonamides/pharmacology , Sulfonamides/therapeutic use
3.
Comb Chem High Throughput Screen ; 15(9): 713-20, 2012 Nov.
Article in English | MEDLINE | ID: mdl-22934951

ABSTRACT

Congenital Insensitivity to Pain (CIP) is a loss of function mutation resulting in a truncated NaV1.7 protein, suggesting a pivotal role in pain signaling and rendering it an important pharmaceutical target for multiple pain conditions. The structural homology in the NaV-channel family makes it challenging to design effective analgesic compounds without inducing for example cardiotoxicity or seizure liabilities. An additional approach to structural isoform selectivity is to identify compounds with use- or state-dependent profiles, i.e. inhibition efficacy based on the gating of the ion channel. In general nerve cells in damaged or inflamed tissue are more depolarized and electrically active compared to healthy nerve cells in for instance the heart. This observation has led to the design of two types of screening protocols emulating the voltage condition of peripheral neurons or cardiac tissue. The two voltage protocols have been developed to identify both use- and state-dependent antagonists. In this paper we describe an attempt to merge the two different protocols into one to increase screening efficacy, while retaining relevant state- and use-dependent pharmacology. The new protocol is constructed of two stimulation pulses and a slow voltage ramp for simultaneous assessment of resting and state-dependent block. By comparing all protocols we show that the new protocol indeed filter compounds for state-dependence and increase the prediction power of selecting use-dependent compounds.


Subject(s)
High-Throughput Screening Assays/methods , NAV1.7 Voltage-Gated Sodium Channel/metabolism , Cells, Cultured , Humans , Molecular Structure , Structure-Activity Relationship
4.
Eur J Pharmacol ; 499(1-2): 67-75, 2004 Sep 19.
Article in English | MEDLINE | ID: mdl-15363952

ABSTRACT

The in vitro pharmacological properties of AR-A000002 ((R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide), a novel 5-hydroxytryptamine (5-HT)(1B) receptor antagonist, were studied. AR-A000002 bound with high affinity to guinea pig cortex and recombinant guinea pig 5-HT(1B) receptors (Ki=0.24 and 0.47 nM) and with 10-fold lower affinity to 5-HT(1D) receptors. The compound displayed weak or no affinity for 63 other binding sites tested. In [35S]GTPgammaS assays AR-A000002 showed 50% efficacy and inhibited 5-HT stimulation with 66% and a pA2 value of 8.9. In slices of guinea pig cortex, AR-A000002 enhanced the outflow of [3H]5-HT upon electrical stimulation. The compound blocked sumatriptan-evoked contraction of rabbit saphenous veins without inducing any contraction itself. Thus, in these two systems AR-A000002 behaved as a 5-HT(1B) receptor antagonist. It is concluded that AR-A000002 is a selective high affinity 5HT(1B) receptor ligand that shows partial agonist activity in recombinant systems. In native tissues AR-A000002 behaves as a 5-HT(1B) receptor antagonist.


Subject(s)
Autoreceptors/antagonists & inhibitors , Benzamides/pharmacology , Morpholines/pharmacology , Serotonin 5-HT1 Receptor Antagonists , Animals , Autoreceptors/metabolism , Benzamides/metabolism , Binding, Competitive/drug effects , Cell Line , Cell Membrane/drug effects , Cell Membrane/metabolism , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Dose-Response Relationship, Drug , Electric Stimulation , Guanosine 5'-O-(3-Thiotriphosphate)/metabolism , Guinea Pigs , Humans , In Vitro Techniques , Indoles/pharmacology , Piperidones/pharmacology , Pyridines/metabolism , Pyridines/pharmacology , Rabbits , Radioligand Assay , Receptor, Serotonin, 5-HT1B/genetics , Receptor, Serotonin, 5-HT1B/metabolism , Receptor, Serotonin, 5-HT1D/metabolism , Saphenous Vein/drug effects , Saphenous Vein/physiology , Serotonin/metabolism , Serotonin/pharmacology , Spiro Compounds/pharmacology , Sulfur Radioisotopes , Sumatriptan/pharmacology , Transfection , Tritium , Vasoconstriction/drug effects , Vasoconstrictor Agents/pharmacology
5.
Brain Pathol ; 13(4): 617-29, 2003 Oct.
Article in English | MEDLINE | ID: mdl-14655765

ABSTRACT

Chemokines are important for the recruitment of immune cells into sites of inflammation. To better understand their functional roles during inflammation we have here studied the in vivo expression of receptors for the chemokines CCL3/CCL5/CCL7 (MIP-1alpha/RANTES/MCP-3) and CX3CL1 (fractalkine), CCR1 and CX3CR1, respectively, in rat myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis. Combined in situ hybridization and immunohistochemistry demonstrated intensely upregulated CCR1 mRNA expression in early, actively demyelinating plaques, whereas CX3CR1 displayed a more generalized expression pattern. CX3CR1 mRNA expressing cells were identified as microglia on the basis of their cellular morphology and positive GSA/B4 lectin staining. In contrast, CCR1 mRNA was preferentially expressed by ED1+ GSA/B4+ macrophages. The notion of differential chemokine receptor expression in microglia and monocyte-derived macrophages was corroborated at the protein level by extraction and flow cytometric sorting of cells infiltrating the spinal cord using gating for the surface markers CD45, ED-2 and CD11b. These observations suggest a differential receptor expression between microglia and monocyte-derived macrophages and that mainly the latter cell type is responsible for active demyelination. This has great relevance for the possibility of therapeutic intervention in demyelinating diseases such as multiple sclerosis, for example by targeting signaling events leading to monocyte recruitment.


Subject(s)
DNA-Binding Proteins , Encephalomyelitis, Autoimmune, Experimental/pathology , Macrophages/metabolism , Microglia/metabolism , Nuclear Proteins , Receptors, Chemokine/metabolism , Receptors, Cytokine/metabolism , Receptors, HIV/metabolism , Animals , CX3C Chemokine Receptor 1 , Disease Models, Animal , Ectodysplasins , Encephalomyelitis, Autoimmune, Experimental/genetics , Encephalomyelitis, Autoimmune, Experimental/metabolism , Female , Flow Cytometry , Hepatocyte Nuclear Factor 1 , Hepatocyte Nuclear Factor 1-alpha , Hepatocyte Nuclear Factor 1-beta , Image Processing, Computer-Assisted , Immunization/methods , Immunohistochemistry , In Situ Hybridization , Lymphocytes/metabolism , Lymphocytes/pathology , Macrophages/pathology , Membrane Proteins/metabolism , Microglia/pathology , Myelin Proteins , Myelin-Associated Glycoprotein/immunology , Myelin-Oligodendrocyte Glycoprotein , RNA, Messenger/biosynthesis , Rats , Rats, Inbred Strains , Receptors, CCR1 , Reverse Transcriptase Polymerase Chain Reaction , Staining and Labeling , Time Factors , Transcription Factors/metabolism
6.
J Neuroimmunol ; 142(1-2): 75-85, 2003 Sep.
Article in English | MEDLINE | ID: mdl-14512166

ABSTRACT

We have studied the role of the chemokine receptor CCR1 during the effector stage of myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis in DA rats. In situ hybridization histochemistry revealed local production of the CCR1 ligands CCL3 (MIP-1 alpha) and CCL5 (RANTES), as well as large numbers of CCR1 and CCR5 expressing cells within inflammatory brain lesions. A low-molecular weight CCR1 selective antagonist potently abrogated both clinical and histopathological disease signs during a 5-day treatment period, without signs of peripheral immune compromise. Thus, we demonstrate therapeutic targeting of CCR1-dependent leukocyte recruitment to the central nervous system in a multiple sclerosis (MS)-like rat model.


Subject(s)
Chemokines, CC/metabolism , Encephalomyelitis, Autoimmune, Experimental/immunology , Encephalomyelitis, Autoimmune, Experimental/prevention & control , Multiple Sclerosis/immunology , Multiple Sclerosis/prevention & control , Receptors, Chemokine/antagonists & inhibitors , Receptors, Chemokine/biosynthesis , Animals , Cell Migration Inhibition , Chemokines, CC/antagonists & inhibitors , Disease Models, Animal , Drug Administration Schedule , Encephalomyelitis, Autoimmune, Experimental/pathology , Female , Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/adverse effects , Injections, Subcutaneous , Lymphoproliferative Disorders/chemically induced , Multiple Sclerosis/pathology , Myelin Proteins , Myelin-Associated Glycoprotein/toxicity , Myelin-Oligodendrocyte Glycoprotein , Nitriles/administration & dosage , Nitriles/adverse effects , Piperazines/administration & dosage , Piperazines/adverse effects , Rats , Receptors, CCR1
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