ABSTRACT
Multiple sclerosis (MS) is a chronic neurological disease characterized by inflammatory demyelination that disrupts neuronal transmission resulting in neurodegeneration progressive disability. While current treatments focus on immunosuppression to limit inflammation and further myelin loss, no approved therapies effectively promote remyelination to mitigate the progressive disability associated with chronic demyelination. Lysophosphatidic acid (LPA) is a pro-inflammatory lipid that is upregulated in MS patient plasma and cerebrospinal fluid (CSF). LPA activates the LPA1 receptor, resulting in elevated CNS cytokine and chemokine levels, infiltration of immune cells, and microglial/astrocyte activation. This results in a neuroinflammatory response leading to demyelination and suppressed remyelination. A medicinal chemistry effort identified PIPE-791, an oral, brain-penetrant, LPA1 antagonist. PIPE-791 was characterized in vitro and in vivo and was found to be a potent, selective LPA1 antagonist with slow receptor off-rate kinetics. In vitro, PIPE-791 induced OPC differentiation and promoted remyelination following a demyelinating insult. PIPE-791 further mitigated the macrophage-mediated inhibition of OPC differentiation and inhibited microglial and fibroblast activation. In vivo, the compound readily crossed the blood-brain barrier and blocked LPA1 in the CNS after oral dosing. Direct dosing of PIPE-791 in vivo increased oligodendrocyte number, and in the mouse experimental autoimmune encephalomyelitis (EAE) model of MS, we observed that PIPE-791 promoted myelination, reduced neuroinflammation, and restored visual evoked potential latencies (VEP). These findings support targeting LPA1 for remyelination and encourage development of PIPE-791 for treating MS patients with advantages not seen with current immunosuppressive disease modifying therapies.
Subject(s)
Multiple Sclerosis , Receptors, Lysophosphatidic Acid , Remyelination , Animals , Multiple Sclerosis/drug therapy , Multiple Sclerosis/metabolism , Receptors, Lysophosphatidic Acid/antagonists & inhibitors , Receptors, Lysophosphatidic Acid/metabolism , Remyelination/drug effects , Humans , Mice , Neuroinflammatory Diseases/drug therapy , Neuroinflammatory Diseases/metabolism , Oligodendroglia/metabolism , Oligodendroglia/drug effects , Brain/metabolism , Brain/drug effects , Brain/pathology , Cell Differentiation/drug effects , Encephalomyelitis, Autoimmune, Experimental/drug therapy , Encephalomyelitis, Autoimmune, Experimental/metabolism , Mice, Inbred C57BL , Myelin Sheath/metabolism , Myelin Sheath/drug effects , Lysophospholipids/metabolism , Blood-Brain Barrier/metabolism , Blood-Brain Barrier/drug effectsABSTRACT
Structure-activity relationship studies on the phenyl ring of 3-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitrile 2 led to the discovery that small, non-hydrogen bond donor substituents at the 3-position led to a substantial increase in in vitro potency. In particular, 3-fluoro-5-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitrile (7) is a highly potent and selective mGlu5 receptor antagonist with good rat pharmacokinetics, brain penetration, and in vivo receptor occupancy.
Subject(s)
Excitatory Amino Acid Antagonists/chemical synthesis , Excitatory Amino Acid Antagonists/pharmacology , Nitriles/chemistry , Nitriles/pharmacology , Pyridines/chemistry , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Tetrazoles/chemistry , Animals , Brain/drug effects , Brain/metabolism , Excitatory Amino Acid Antagonists/chemistry , Kinetics , Mice , Molecular Structure , Rats , Receptor, Metabotropic Glutamate 5 , Receptors, Metabotropic Glutamate/metabolism , Sensitivity and Specificity , Structure-Activity Relationship , Substrate SpecificityABSTRACT
Structure-activity relationship studies on 3-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitrile 2 led to the discovery of 2-(2-[3-(pyridin-3-yloxy)phenyl]-2H-tetrazol-5-yl)pyridine (10)-a highly potent and selective mGlu5 receptor antagonist with good brain penetration and in vivo receptor occupancy in rat and cross-species oral bioavailability.
Subject(s)
Anti-Anxiety Agents/pharmacokinetics , Nitriles/pharmacokinetics , Pyridines/chemistry , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Tetrazoles/chemistry , Tetrazoles/pharmacokinetics , Administration, Oral , Animals , Anti-Anxiety Agents/administration & dosage , Anti-Anxiety Agents/chemistry , Biological Availability , Dogs , Dose-Response Relationship, Drug , Haplorhini , Molecular Structure , Nitriles/chemistry , Pyridines/pharmacokinetics , Rats , Receptor, Metabotropic Glutamate 5 , Structure-Activity RelationshipABSTRACT
Structure-activity relationship studies focused on bio-isosteric replacements of 2-pyridyl resulted in mGlu5 receptor antagonists with reduced inhibition of cytochrome P450 1A2. This led to highly potent, selective and orally bioavailable 2-imidazolyl tetrazoles such as (10) that are devoid of cytochrome P450 inhibitory activity.
Subject(s)
Cytochrome P-450 CYP1A2 Inhibitors , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Tetrazoles/chemical synthesis , Tetrazoles/pharmacokinetics , Administration, Oral , Animals , Anti-Anxiety Agents/chemical synthesis , Anti-Anxiety Agents/chemistry , Anti-Anxiety Agents/pharmacokinetics , Biological Availability , Molecular Structure , Rats , Rats, Sprague-Dawley , Receptor, Metabotropic Glutamate 5 , Structure-Activity Relationship , Tetrazoles/chemistryABSTRACT
Structure-activity relationship studies leading to the discovery of a new, orally active mGlu5 receptor antagonist are described. The title compound, 5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-2,3'-bipyridine, is highly potent in vitro, has good in vivo receptor occupancy, and is efficacious in the rat fear-potentiated startle model of anxiety following oral dosing.
