Neurodegenerative
proteinopathies are characterized by the intracellular
formation of insoluble and toxic protein aggregates in the brain that
are closely linked to disease progression. In Alzheimer’s disease
and in rare tauopathies, aggregation of the microtubule-associated
tau protein leads to the formation of neurofibrillary tangles (NFT).
In Parkinson’s disease (PD) and other α-synucleinopathies,
intracellular Lewy bodies containing aggregates of α-synuclein
constitute the pathological hallmark. Inhibition of the glycoside
hydrolase O-GlcNAcase (OGA) prevents the removal of O-linked
N
-acetyl-
d
-glucosamine (O-GlcNAc) moieties from
intracellular proteins and has emerged as an attractive therapeutic
approach to prevent the formation of tau pathology. Like tau, α-synuclein
is known to be modified with O-GlcNAc moieties and
in vitro
these have been shown to prevent its aggregation and toxicity. Here,
we report the preclinical discovery and development of a novel small
molecule OGA inhibitor, ASN90. Consistent with the substantial exposure
of the drug and demonstrating target engagement in the brain, the
clinical OGA inhibitor ASN90 promoted the O-GlcNAcylation of tau and
α-synuclein in brains of transgenic mice after daily oral dosing.
Across human tauopathy mouse models, oral administration of ASN90
prevented the development of tau pathology (NFT formation), functional
deficits in motor behavior and breathing, and increased survival.
In addition, ASN90 slowed the progression of motor impairment and
reduced astrogliosis in a frequently utilized α-synuclein-dependent
preclinical rodent model of PD. These findings provide a strong rationale
for the development of OGA inhibitors as disease-modifying agents
in both tauopathies and α-synucleinopathies. Since tau and α-synuclein
pathologies frequently co-exist in neurodegenerative diseases, OGA
inhibitors represent unique, multimodal drug candidates for further
clinical development.
We have discovered a new, potent, selective, and orally active oxytocin receptor antagonist, (2S,4Z)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2Ј-methyl[1,1Ј-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide (compound 1).We report the biochemical, pharmacological, and pharmacokinetic characterization in vitro and in vivo of this compound. Premature birth is a major problem in obstetrics affecting about 10% of all births and being the largest cause of perinatal morbidity and mortality. The impact on society is significant in terms of costs of neonatal intensive care and for the emotional and social stress to the family. The physiopathology of human preterm labor is complex and multifactorial. Preterm increase of uterine activity is a common complication of pregnancy and accounts for many cases of preterm labor. Pharmacological interventions aimed at maintaining uterine quiescence (tocolysis) have been, and are likely to remain, the cornerstone of pharmaceutical management of preterm labor. However, current tocolytic agents (-mimetics, magnesium sulfate, calcium channel blockers, or prostaglandin synthesis inhibitors) suffer from a minimal effectiveness and show important fetal and maternal side effects. Therefore, it is obvious that a safe and effective oral treatment delaying spontaneous preterm birth would have tremendous clinical benefits.The peptide hormone oxytocin (OT) is a potent contractor of the human uterus. OT mediates its effect through activation of the G protein-coupled oxytocin receptor (OT-R) that is expressed in myometrial cells. OT-R is coupled to phospholipase C activation, leading to intracellular synthesis of inositol phosphates and mobilization of calcium. In turn, the rise in intracellular calcium concentration promotes a cascade of events, including phosphorylation of myosin, that then acts on actin and induces uterine muscle cell contraction. Before onset of labor and in the term myometrium, the OT-R density Article, publication date, and citation information can be found at
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