Multiple sclerosis (MS) is a chronic autoimmune, inflammatory disease of the central nervous system (CNS), which causes damage to myelin and axons, resulting in neurological symptoms such as partial loss of sight, paresthesias and ataxia.
Figure showing the neurobiology of demyelination and axon degeneration associated with Multiple Sclerosis.
Adapted from the Multiple Sclerosis poster, written by Dr Wilkins and Dr Ibitoye 2016.
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BX471 is a potent, selective, non-peptide CCR1 antagonist with Ki of 1 nM for hCCR1, displays 100 times less affinity for rat CCR1; shows 10,000-fold selectivity for CCR1 compared with 28 GPCRs (); displays CCR1 ligands MIP-1α, RANTES, and MCP-3 with high affinity (Ki=1-5.5 nM), inhibits a number of CCR1-mediated effects including Ca(2+) mobilization, increase in extracellular acidification rate, CD11b expression; effectively reduces disease in a rat experimental allergic encephalomyelitis model of multiple sclerosis.
Fingolimod (FTY 720) is an immunomodulatory agent can be phosphorylated by SphK, then functions as a potent agonist of S1P receptors (S1P1/3/4/5) with EC50 of 0.3-5 nM; has no affitnity for S1P2; alters lymphocyte trafficking and inhibits lymphocyte recirculation.
A potent, selective, orally active S1P1 receptor agonist with EC50 of 9.1 nM; shows weak activity on S1P3 (EC50=123 nM); activates S1P1-mediated signal transduction with high potency (EC50 of 5.7 nM); causes maximal reduction of circulating lymphocytes at a dose of 3 mg/kg.
Siponimod (BAF312) is a potent, selective S1P1/S1P5 receptor modulator with EC50 of 0.39/0.0.98 nM, >1,000-fold selectivity over S1P2/3/4; suppresses ongoing disease symptoms in rat EAE, concentration-dependently increases GIRK current amplitude in atrial myocytes with EC50 of 15.8 nM, reduces peripheral absolute lymphocyte counts in vivo, exhibits potential as a treatment for immune-mediated diseases.
An immunomodulatory agent can be phosphorylated by SphK, then functions as a potent agonist of S1P receptors (S1P1/3/4/5) with EC50 of 0.3-5 nM; has no affitnity for S1P2; alters lymphocyte trafficking and inhibits lymphocyte recirculation.
Laquinimod (ABR-215062) is an immunoregulator derived from Linomide, has been shown to completely inhibit the development of murine acute experimental autoimmune encephalomyelitis (EAE); dose-dependently reduces the incidence of EAN, ameliorated clinical signs and inhibited P0 peptide 180-199-specific T cell responses as well as also the decreased inflammation and demyelination in the peripheral nerves; shows improved potency and superior toxicological profile compared to the lead compound Roquinimex (Linomide).
AZD5904 (AZD-5904) is a potent, selective irreversible, orally bioavailable myeloperoxidase (MPO) inhibitor with IC50 of 140 nM, similar potency in mouse and rat; displays 10 to 19-fold selective compared to the closely related lactoperoxidase and thyroid peroxidase, >70-fold to a broad panel of other enzymes, ion channels, and receptors; 1 µM AZD5904 inhibited PMA stimulated HOCl by >90% in isolated human neutrophils; a plasma concentration of ~5 µM decreased the in vivo formation of glutathione sulphonamide in rats.
Ozanimod (RPC-1063) is a potent, selective agonist of S1P1 and S1P5 receptor with EC50 of 0.41 nM and 11 nM respectively; less potent for S1P2, S1P3 and S1P4 (EC50> 10 uM); induces S1P1 receptor internalization and induced a reversible reduction in circulating B and CCR7(+) T lymphocytes in vivo; shows high oral bioavailability and volume of distribution, and a circulatory half-life.
Plerixafor octahydrochloride (JM-3100, AMD-3100, SID-791) is a potent, selective CXCR4 inhibitor (IC50=44 nM) that inhibits the replication of various HIV-1 and HIV-2 strains in various cell lines with EC50 of 10ng/ml; can produce mesenchymal stem cells and endothelial progenitor cells in mice in combination with VEGF; also is an allosteric agonist of CXCR7.
A novel prodrug S1P receptor modulator lacking S1P3 receptor agonism to avoid bradycardia associated with fingolimod and other S1P receptor modulators; the selectivity of the active metabolite amiselimod phosphate (Amiselimod-P) shows potent selectivity for S1P1 and high selectivity for S1P5 receptors, with minimal agonist activity for S1P4 and no distinct agonist activity for S1P2 or S1P3 receptors and approximately five-fold weaker GIRK activation than fingolimod-P; exhibits potent therapeutic efficacy with minimal cardiac effects.
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