Clinical human genetic studies have recently identified the tetrodotoxin (TTX) sensitive neuronal voltage gated sodium channel Nav1.7 (SCN9A) as a critical mediator of pain sensitization. Herein, we report structure-activity relationships for a novel series of 2,4-diaminotriazines that inhibit hNav1.7. Optimization efforts culminated in compound 52, which demonstrated pharmacokinetic properties appropriate for in vivo testing in rats. The binding site of compound 52 on Nav1.7 was determined to be distinct from that of local anesthetics. Compound 52 inhibited tetrodotoxin-sensitive sodium channels recorded from rat sensory neurons and exhibited modest selectivity against the hERG potassium channel and against cloned and native tetrodotoxin-resistant sodium channels. Upon oral administration to rats, compound 52 produced dose- and exposure-dependent efficacy in the formalin model of pain.

The optimization of a series of aminooxazoline xanthene inhibitors of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is described. An early lead compound showed robust Aβ lowering activity in a rat pharmacodynamic model, but advancement was precluded by a low therapeutic window to QTc prolongation in cardiovascular models consistent with in vitro activity on the hERG ion channel. While the introduction of polar groups was effective in reducing hERG binding affinity, this came at the expense of higher than desired Pgp-mediated efflux. A balance of low Pgp efflux and hERG activity was achieved by lowering the polar surface area of the P3 substituent while retaining polarity in the P2' side chain. The introduction of a fluorine in position 4 of the xanthene ring improved BACE1 potency (5-10-fold). The combination of these optimized fragments resulted in identification of compound 40, which showed robust Aβ reduction in a rat pharmacodynamic model (78% Aβ reduction in CSF at 10 mg/kg po) and also showed acceptable cardiovascular safety in vivo.

BACE1 inhibition to prevent Aβ peptide formation is considered to be a potential route to a diseasemodifying treatment for Alzheimer's disease. Previous efforts in our laboratory using a combined structure-and propertybased approach have resulted in the identification of aminooxazoline xanthenes as potent BACE1 inhibitors. Herein, we report further optimization leading to the discovery of inhibitor 15 as an orally available and highly efficacious BACE1 inhibitor that robustly reduces CSF and brain Aβ levels in both rats and nonhuman primates. In addition, compound 15 exhibited low activity on the hERG ion channel and was well tolerated in an integrated cardiovascular safety model. KEYWORDS: β-site amyloid precursor protein cleaving enzyme 1 (BACE1), Alzheimer's disease (AD), Aβ, aminooxazoline, xanthene A lzheimer's disease (AD) is the most common neurodegenerative disorder and accounts for 50−80% of dementia cases identified each year. Current therapeutics for AD only provide temporary symptomatic relief and do not address the underlying neuropathology. A therapeutic treatment that directly modifies the progression of the disease remains one of the largest unmet medical needs in neurobiology.The most widely held hypothesis for the underlying pathogenesis of AD posits that aggregation of β-amyloid peptides (Aβ) and deposition into amyloid plaques in the neural parenchyma play an essential role. Aβ is produced by sequential endoproteolytic cleavage of amyloid precursor protein (APP) by the aspartyl protease β-site APP cleaving enzyme-1 (BACE1) and γ-secretase.

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Through analyzing the motion when motorcycle runs on the bump road, the 5-DOF multi-body dynamics model of motorcycle is developed, the degrees of freedom include vertical displacement of sprung mass, rotation of sprung mass, vertical displacement of driver, and vertical displacement of front and rear suspension under sprung mass. According to Lagrange Equation, the differential equations of motion and state-space formulation are derived. Then bump road is simulated by triangle bump, and input displacement is programmed by MATLAB. With the input of bump road, motorcycle ride comfort is simulated, and the simulation results are verified by experiment results combined with two channels tire-coupling road simulator. It indicates that the simulation results and experiment results match well; the 5-DOF model has guidance for development of motorcycle ride comfort.