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.
Structure–activity relationship studies led to the discovery of PIPE-3297, a fully efficacious and selective kappa opioid receptor (KOR) agonist. PIPE-3297, a potent activator of G-protein signaling ...(GTPγS EC50 = 1.1 nM, 91% E max), did not elicit a β-arrestin-2 recruitment functional response (E max < 10%). Receptor occupancy experiments performed with the novel KOR radiotracer 3H-PIPE-3113 revealed that subcutaneous (s.c.) administration of PIPE-3297 at 30 mg/kg in mice achieved 90% occupancy of the KOR in the CNS 1 h post dose. A single subcutaneous dose of PIPE-3297 in healthy mice produced a statistically significant increase of mature oligodendrocytes (P < 0.0001) in the KOR-enriched striatum, an effect that was not observed in animals predosed with the selective KOR antagonist norbinaltorphimine. An equivalent dose given to mice in an open-field activity-monitoring system revealed a small KOR-independent decrease in total locomotor activity versus vehicle measured between 60 and 75 min post dose. Daily doses of PIPE-3297 at both 3 and 30 mg/kg s.c. reduced the disease score in the mouse experimental autoimmune encephalomyelitis (EAE) model. Visually evoked potential (VEP) N1 latencies were also significantly improved versus vehicle in both dose groups, and latencies matched those of untreated animals. Taken together, these findings highlight the potential therapeutic value of functionally selective G-protein KOR agonists in demyelinating disease, which may avoid the sedating side effects typically associated with classical nonbiased KOR agonists.
Two distinct and scalable enantioselective approaches to the tricyclic indole (R)-2-(7-hydroxy-2,3-dihydro-1H-pyrrolo1,2-aindol-1-yl)acetate, an important synthon for a preclinical S1P1 receptor ...agonist, are reported. Route 1 employs a modified version of Smith’s modular 2-substituted indole synthesis as the key transformation. Route 2 involves a highly enantioselective CuH-catalyzed 1,4-hydrosilylation as the stereodefining step. Both routes can be performed without chromatography to provide multigram quantities of the tricycle in ≥98% ee.
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A series of novel (R)-6,6a,7,8,9,10-hexahydro-5H-pyrazino1,2-a1,nnaphthyridines were identified as potent and selective agonists of the 5-HT2C receptor. Optimizations performed on a ...previously reported series of racemic tetrahydroquinoline-based tricyclic amines, delivered an advanced drug lead, (R)-4-(3,3,3-trifluoropropyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino1,2-a1,8naphthyridine, which displayed excellent in vitro and in vivo pharmacological profiles.
The discovery of PIPE-359, a brain-penetrant and selective antagonist of the muscarinic acetylcholine receptor subtype 1 is described. Starting from a literature-reported M
antagonist, linker ...replacement and structure-activity relationship investigations of the eastern 1-(pyridinyl)piperazine led to the identification of a novel, potent, and selective antagonist with good MDCKII-MDR1 permeability. Continued semi-iterative positional scanning facilitated improvements in the metabolic and hERG profiles, which ultimately delivered PIPE-359. This advanced drug candidate exhibited robust efficacy in mouse myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalitis (EAE), a preclinical model for multiple sclerosis.
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A series of potential new 5-HT2 receptor scaffolds based on a simplification of the clinically studied, 5-HT2CR agonist vabicaserin, were designed. An in vivo feeding assay early in ...our screening process played an instrumental part in the lead identification process, leading us to focus on a 6,5,7-tricyclic scaffold. A subsequent early SAR investigation provided potent agonists of the 5-HT2C receptor that were highly selective in both functional and binding assays, had good rat PK properties and that significantly reduced acute food intake in the rat.
The
discovery of PIPE-359, a brain-penetrant and selective antagonist
of the muscarinic acetylcholine receptor subtype 1 is described. Starting
from a literature-reported M
1
antagonist, linker ...replacement
and structure–activity relationship investigations of the eastern
1-(pyridinyl)piperazine led to the identification of a novel, potent,
and selective antagonist with good MDCKII-MDR1 permeability. Continued
semi-iterative positional scanning facilitated improvements in the
metabolic and hERG profiles, which ultimately delivered PIPE-359.
This advanced drug candidate exhibited robust efficacy in mouse myelin
oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune
encephalitis (EAE), a preclinical model for multiple sclerosis.
The syntheses, structure-activity relationships (SARs), and biological activities of tetrahydroquinoline-based tricyclic amines as 5-HT
receptor agonists are reported. An early lead containing a ...highly unique 6,6,7-ring system was optimized for both in vitro potency and selectivity at the related 5-HT
receptor. Orally bioactive, potent, and selective 6,6,6-tricyclic 5-HT
agonists were identified.
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The syntheses, structure-activity relationships (SARs), and biological activities of tetrahydroquinoline-based tricyclic amines as 5-HT2C receptor agonists are reported. An early lead ...containing a highly unique 6,6,7-ring system was optimized for both in vitro potency and selectivity at the related 5-HT2B receptor. Orally bioactive, potent, and selective 6,6,6-tricyclic 5-HT2C agonists were identified.
The discovery and profiling of 3-(1H-tetrazol-5-yl)-1,4,5,6-tetrahydro-cyclopentapyrazole (5a, MK-0354), a partial agonist of GPR109a, is described. Compound 5a retained the plasma free fatty acid ...lowering effects in mice associated with GPR109a agonism, but did not induce vasodilation at the maximum feasible dose. Moreover, preadministration of 5a blocked the flushing effect induced by nicotinic acid but not that induced by PGD2. This profile made 5a a suitable candidate for further study for the treatment of dyslipidemia.
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