Hallmarks of neurodegenerative disease: A systems pharmacology perspective.

Age-related central neurodegenerative diseases, such as Alzheimer's and Parkinson's disease, are a rising public health concern and have been plagued by repeated drug development failures. The complex nature and poor mechanistic understanding of the etiology of neurodegenerative diseases has hindered the discovery and development of effective disease-modifying therapeutics. Quantitative systems pharmacology models of neurodegeneration diseases may be useful tools to enhance the understanding of pharmacological intervention strategies and to reduce drug attrition rates. Due to the similarities in pathophysiological mechanisms across neurodegenerative diseases, especially at the cellular and molecular levels, we envision the possibility of structural components that are conserved across models of neurodegenerative diseases. Conserved structural submodels can be viewed as building blocks that are pieced together alongside unique disease components to construct quantitative systems pharmacology (QSP) models of neurodegenerative diseases. Model parameterization would likely be different between the different types of neurodegenerative diseases as well as individual patients. Formulating our mechanistic understanding of neurodegenerative pathophysiology as a mathematical model could aid in the identification and prioritization of drug targets and combinatorial treatment strategies, evaluate the role of patient characteristics on disease progression and therapeutic response, and serve as a central repository of knowledge. Here, we provide a background on neurodegenerative diseases, highlight hallmarks of neurodegeneration, and summarize previous QSP models of neurodegenerative diseases.

Multiscale Computer Model of the Spinal Dorsal Horn Reveals Changes in Network Processing Associated with Chronic Pain.

Pain-related sensory input is processed in the spinal dorsal horn (SDH) before being relayed to the brain. That processing profoundly influences whether stimuli are correctly or incorrectly perceived as painful. Significant advances have been made in identifying the types of excitatory and inhibitory neurons that comprise the SDH, and there is some information about how neuron types are connected, but it remains unclear how the overall circuit processes sensory input or how that processing is disrupted under chronic pain conditions. To explore SDH function, we developed a computational model of the circuit that is tightly constrained by experimental data. Our model comprises conductance-based neuron models that reproduce the characteristic firing patterns of spinal neurons. Excitatory and inhibitory neuron populations, defined by their expression of genetic markers, spiking pattern, or morphology, were synaptically connected according to available qualitative data. Using a genetic algorithm, synaptic weights were tuned to reproduce projection neuron firing rates (model output) based on primary afferent firing rates (model input) across a range of mechanical stimulus intensities. Disparate synaptic weight combinations could produce equivalent circuit function, revealing degeneracy that may underlie heterogeneous responses of different circuits to perturbations or pathologic insults. To validate our model, we verified that it responded to the reduction of inhibition (i.e., disinhibition) and ablation of specific neuron types in a manner consistent with experiments. Thus validated, our model offers a valuable resource for interpreting experimental results and testing hypotheses in silico to plan experiments for examining normal and pathologic SDH circuit function.SIGNIFICANCE STATEMENT We developed a multiscale computer model of the posterior part of spinal cord gray matter (spinal dorsal horn), which is involved in perceiving touch and pain. The model reproduces several experimental observations and makes predictions about how specific types of spinal neurons and synapses influence projection neurons that send information to the brain. Misfiring of these projection neurons can produce anomalous sensations associated with chronic pain. Our computer model will not only assist in planning future experiments, but will also be useful for developing new pharmacotherapy for chronic pain disorders, connecting the effect of drugs acting at the molecular scale with emergent properties of neurons and circuits that shape the pain experience.

In vitro inhibition and enhancement of liver microsomal S-777469 metabolism by long-chain fatty acids and serum albumin: insight into in vitro and in vivo discrepancy of metabolite formation in humans.

1. It was previously demonstrated that 10% of S-777469, a cannabinoid receptor 2 selective agonist, is metabolized to its carboxylic acid metabolite (S-777469 5-carboxylic acid, 5-CA) in humans in vivo, while the formation of 5-CA is extremely low in human cryopreserved hepatocytes and liver microsomes (HLMs). In this study, factors causing the different metabolite formation rates of S-777469 in vitro and in vivo were investigated. 2. Formation of 5-CA and S-777469 5-hydroxymethyl (5-HM), a precursor metabolite of 5-CA, was catalyzed by CYP2C9. Arachidonic acid, α-linolenic acid, oleic acid and myristic acid, which have been reported to exist in liver microsomes, inhibited S-777469 oxidation by CYP2C9, but serum albumin enhanced this reactions. 3. The IC50 values of these fatty acids for 5-CA formation from 5-HM were lower than those of 5-HM formation from S-777469. Serum albumin extensively enhanced 5-CA formation from 5-HM in comparison to 5-HM formation from S-777469. 4. CYP2C9 was the enzyme responsible for S-777469 oxidation in human livers. The suppressive effects of several fatty acids and enhancing action of serum albumin in vitro are likely to be the causal factors for the apparently different rates of in vitro and in vivo metabolite formation of S-777469.

The metabolism and pharmacokinetics of [14C]-S-777469, a new cannabinoid receptor 2 selective agonist, in healthy human subjects.

1. The metabolism and pharmacokinetics of S-777469 were investigated after a single oral administration of [14C]-S-777469 to healthy human subjects. 2. Total radioactivity was rapidly and well absorbed in humans, with Cmax of 11,308 ng eq. of S-777469/ml at 4.0 h. The AUCinf ratio of unchanged S-777469 to total radioactivity was approximately 30%, indicating that S-777469 was extensively metabolized in humans. 3. The metabolite profiling in human plasma showed that S-777469 5-carboxymethyl (5-CA) and S-777469 5-hydroxymethyl (5-HM) were the main circulating metabolites, and the AUCinf ratio of 5-CA and 5-HM to total radioactivity were 24 and 9.1%, respectively. These data suggest that S-777469 was subsequently metabolized to 5-CA in humans although the production amount of 5-CA was extremely low in human hepatocytes. 4. Total radioactivity was mainly excreted via the feces, with 5-CA and 5-HM being the main excretory metabolites in feces and urine. Urinary excretion of 5-CA was comparable with that of 5-HM, whereas fecal excretion of 5-CA was lower than that of 5-HM. 5. In conclusion, the current mass balance study revealed the metabolic and pharmacokinetic properties of S-777469 in humans. These data should be useful to judge whether or not the safety testing of metabolite of S-777469 is necessary.

Non-clinical evaluation of the metabolism, pharmacokinetics and excretion of S-777469, a new cannabinoid receptor 2 selective agonist.

1. The drug metabolism and pharmacokinetics of S-777469 were investigated in in vitro (rat, dog and human) and in in vivo (rats and dogs). 2. S-777469 was rapidly and well absorbed, with bioavailability values ranging from 50 to 70% in rats and dogs, almost all drug radioactivity was excreted into the feces via bile within 48 h. Thus, good pharmacokinetics of S-777469 (e.g. systemic exposure and excretion rate) would be anticipated in humans. 3. In vitro metabolism of S-777469 was qualitatively similar in rat, dog and human hepatocytes. S-777469 acyl glucuronide, S-777469 5-hydroxymethyl and S-777469 4-hydroxycyclohexane were the main metabolites in rats, dogs and humans. In vivo metabolism in rats and dogs showed good qualitative agreement with in vitro metabolism, and no metabolites exceeded 10% of total radioactivity in rat and dog plasma. 4. No unique metabolites were observed in human hepatocytes. Therefore, rats and dogs were thought to be appropriate species for non-clinical toxicity studies. 5. In conclusion, these data should be useful for the characterization of the pharmacokinetic properties of S-777469 and the estimation of its pharmacokinetic fate in humans.

Hit to lead SAR study on benzoxazole derivatives for an NPY Y5 antagonist.

We report a hit to lead study on a novel benzoxazole NPY Y5 antagonist. Starting from HTS hit 1, structure-activity relationships were developed. Compound 12 showed reduction of food intake and a tendency to suppress body weight gain over the 21-day experimental period.