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1.
ChemMedChem ; 10(4): 688-714, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25735812

ABSTRACT

Sphingosine-1-phosphate (S1P) receptor agonists have shown promise as therapeutic agents for multiple sclerosis (MS) due to their regulatory roles within the immune, central nervous system, and cardiovascular system. Here, the design and optimization of novel [1,2,4]oxadiazole derivatives as selective S1P receptor agonists are described. The structure-activity relationship exploration was carried out on the three dominant segments of the series: modification of the polar head group (P), replacement of the oxadiazole linker (L) with different five-membered heterocycles, and the use of diverse 2,2'-disubstituted biphenyl moieties as the hydrophobic tail (H). All three segments have a significant impact on potency, S1P receptor subtype selectivity, physicochemical properties, and in vitro absorption, distribution, metabolism, excretion and toxicity (ADMET) profile of the compounds. From these optimization studies, a selective S1P1 agonist, N-methyl-N-(4-{5-[2-methyl-2'-(trifluoromethyl)biphenyl-4-yl]-1,2,4-oxadiazol-3-yl}benzyl)glycine (45), and a dual S1P1,5 agonist, N-methyl-N-(3-{5-[2'-methyl-2-(trifluoromethyl)biphenyl-4-yl]-1,2,4-oxadiazol-3-yl}benzyl)glycine (49), emerged as frontrunners. These compounds distribute predominantly in lymph nodes and brain over plasma and induce long lasting decreases in lymphocyte count after oral administration. When evaluated head-to-head in an experimental autoimmune encephalomyelitis mouse model, together with the marketed drug fingolimod, a pan-S1P receptor agonist, S1P1,5 agonist 49 demonstrated comparable efficacy while S1P1 -selective agonist 45 was less potent. Compound 49 is not a prodrug, and its improved property profile should translate into a safer treatment of relapsing forms of MS.


Subject(s)
Drug Design , Encephalomyelitis, Autoimmune, Experimental/drug therapy , Immunologic Factors/chemistry , Immunologic Factors/therapeutic use , Oxadiazoles/chemistry , Oxadiazoles/therapeutic use , Receptors, Lysosphingolipid/agonists , Animals , Encephalomyelitis, Autoimmune, Experimental/immunology , Female , Humans , Immunologic Factors/pharmacokinetics , Mice , Mice, Inbred C57BL , Models, Molecular , Multiple Sclerosis/drug therapy , Oxadiazoles/pharmacokinetics , Receptors, Lysosphingolipid/immunology , Structure-Activity Relationship
2.
Front Immunol ; 5: 233, 2014.
Article in English | MEDLINE | ID: mdl-24904582

ABSTRACT

SLE is a complex autoimmune inflammatory disease characterized by pathogenic autoantibody production as a consequence of uncontrolled T-B cell activity and immune-complex deposition in various organs, including kidney, leading to tissue damage and function loss. There is a high unmet need for better treatment options other than corticosteroids and immunosuppressants. Phosphoinositol-3 kinase δ (PI3Kδ) is a promising target in this respect as it is essential in mediating B- and T-cell function in mouse and human. We report the identification of selective PI3Kδ inhibitors that blocked B-, T-, and plasmacytoid dendritic cell activities in human peripheral blood and in primary cell co-cultures (BioMAP(®)) without detecting signs of undesired toxicity. In an IFNα-accelerated mouse SLE model, our PI3Kδ inhibitors blocked nephritis development, whether administered at the onset of autoantibody appearance or the onset of proteinuria. Disease amelioration correlated with normalized immune cell numbers in the spleen, reduced immune-complex deposition as well as reduced inflammation, fibrosis, and tissue damage in the kidney. Improvements were similar to those achieved with a frequently prescribed drug for lupus nephritis, the potent immunosuppressant mycophenolate mofetil. Finally, we established a pharmacodynamics/pharmacokinetic/efficacy model that revealed that a sustained PI3Kδ inhibition of 50% is sufficient to achieve full efficacy in our disease model. These data demonstrate the therapeutic potential of PI3Kδ inhibitors in SLE and lupus nephritis.

3.
ACS Med Chem Lett ; 4(11): 1037-41, 2013 Nov 14.
Article in English | MEDLINE | ID: mdl-24900603

ABSTRACT

Recent observations on the emergence of artemisinin resistant parasites have highlighted the need for new antimalarial treatments. An HTS campaign led to the identification of the 1-(1-aminopropan-2-ol)carbazole analogues as potent hits against Plasmodium falciparum K1 strain. The SAR study and optimization of early ADME and physicochemical properties direct us to the selection of a late lead compound that shows good efficacy when orally administrated in the in vivo P. berghei mouse model.

4.
EMBO Mol Med ; 2(12): 504-15, 2010 Dec.
Article in English | MEDLINE | ID: mdl-21064192

ABSTRACT

Apoptosis signal-regulating kinase 1 (ASK1) is an evolutionarily conserved mitogen-activated protein kinase (MAPK) kinase kinase which plays important roles in stress and immune responses. Here, we show that ASK1 deficiency attenuates neuroinflammation in experimental autoimmune encephalomyelitis (EAE), without affecting the proliferation capability of T cells. Moreover, we found that EAE upregulates expression of Toll-like receptors (TLRs) in activated astrocytes and microglia, and that TLRs can synergize with ASK1-p38 MAPK signalling in the release of key chemokines from astrocytes. Consequently, oral treatment with a specific small molecular weight inhibitor of ASK1 suppressed EAE-induced autoimmune inflammation in both spinal cords and optic nerves. These results suggest that the TLR-ASK1-p38 pathway in glial cells may serve as a valid therapeutic target for autoimmune demyelinating disorders including multiple sclerosis.


Subject(s)
Demyelinating Diseases/metabolism , MAP Kinase Kinase Kinase 5/metabolism , Signal Transduction , Toll-Like Receptors/metabolism , p38 Mitogen-Activated Protein Kinases/metabolism , Animals , Brain Diseases/drug therapy , Brain Diseases/genetics , Brain Diseases/immunology , Brain Diseases/metabolism , Chemokines/immunology , Demyelinating Diseases/drug therapy , Demyelinating Diseases/genetics , Demyelinating Diseases/immunology , Disease Models, Animal , Encephalitis , Enzyme Inhibitors/administration & dosage , Female , Gene Expression Regulation , Hashimoto Disease/drug therapy , Hashimoto Disease/genetics , Hashimoto Disease/immunology , Hashimoto Disease/metabolism , Humans , MAP Kinase Kinase Kinase 5/antagonists & inhibitors , MAP Kinase Kinase Kinase 5/genetics , Male , Mice , Mice, Inbred C57BL , Neuroglia/metabolism , Rats , Rats, Sprague-Dawley , Toll-Like Receptors/genetics , p38 Mitogen-Activated Protein Kinases/genetics
7.
Comb Chem High Throughput Screen ; 6(7): 577-87, 2003 Nov.
Article in English | MEDLINE | ID: mdl-14683488

ABSTRACT

Advances in high throughput screening (HTS), together with the rapid progress in combinatorial chemistry, genomic and proteomic sciences have dramatically stimulated the development of a variety tools to enable the drug discovery process to become more efficient. Major future challenges in HTS include obtaining high density and good quality data based on assays that are rapid, reliable, inexpensive, sensitive, simple and miniaturised. This paper reviews the development and role of bead-based assays for HTS including DNA and single nucleotide polymorphism (SNP) assays, particularly from a multiplex perspective and evaluating the recent advances in bead-based arrays. The encoding strategies that are commonly used in bead-based assays are highlighted, while the importance of magnetic beads in genomic and proteomic purifications is discussed. In conclusion, bead-based assays offer a powerful promising approach for many aspects of drug discovery.


Subject(s)
Drug Evaluation, Preclinical/methods , Microspheres , Combinatorial Chemistry Techniques , DNA/analysis , Genomics/methods , Proteins/analysis , Proteomics/methods
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