Effects of data sparsity and spatiotemporal variability on hazard maps of workplace noise.

Personal sampling, considered a state-of-the-art technique to assess worker exposures to occupational hazards, is often conducted for the duration of a work shift so that time-weighted average (TWA) exposures may be evaluated relative to published occupational exposure limits (OELs). Such cross-shift measurements, however, provide little information on the spatial variability of exposures, except after a very large number of samples. Hazard maps, contour plots (or similar depiction) of hazard intensity throughout the workplace, have gained popularity as a way to locate sources and to visualize spatial variability of physical and chemical hazards within a facility. However, these maps are often generated from short duration measures and have little ability to assess temporal variability. To assess the potential bias that results from the use of short-duration measurements to represent the TWA in a hazard map, noise intensity measurements were collected at high spatial and temporal resolution in two facilities. Static monitors were distributed throughout the facility and used to capture the temporal variability at these locations. Roving monitors (typical of the hazard mapping process) captured spatial variability over multiple traverses through the facility. The differences in hazards maps generated with different sampling techniques were evaluated. Hazard maps produced from sparse, roving monitor data were in good agreement with the TWA hazard maps at the facility with low temporal variability. Estimated values were within 5 dB of the TWA over approximately 90% of the facility. However, at the facility with higher temporal variability, large differences between hazard maps were observed for different traverses through the facility. On the second day of sampling, estimates were at least 5 dB different than the TWA for more than half of the locations within the facility. The temporal variability of noise was found to have a greater influence on map accuracy than the spatial sampling resolution.

Identification of novel series of human CCR1 antagonists.

A hit-to-lead optimization process was carried out on the high throughput screening hit compound 1 resulting in the identification of several potent and selective CCR1 receptor antagonists. Compound 37 shows the best overall profile with IC(50) values of <100 nM in binding and functional assays.

2-Aryl-N-acyl indole derivatives as liver X receptor (LXR) agonists.

Structure-activity relationship studies on a series of Boc-indole derivatives as LXR agonists are described. Compound 1 was identified as an LXR agonist through structure-based virtual screening followed by high-throughput gene profiling. Replacement of the indan linker portion in 1 with an open-chain linker resulted in compounds with similar or improved in vitro potency and cellular functional activity. The Boc group at the N-1 position of the indole moiety can be replaced with a benzoyl group. The SAR studies led to the identification of compound 8, a potent LXRbeta agonist with an EC50 of 12 nM in the cofactor recruitment assay.

Structure-activity relationships of novel, highly potent, selective, and orally active CCR1 antagonists.

Design and synthesis of a series of 3-amino-4-(2-(2-(4-benzylpiperazin-1-yl)-2-oxoethoxy)phenylamino)cyclobutenedione derivatives as novel CCR1 antagonists are described. Structure-activity relationship studies led to the identification of compound 22, which demonstrated potent binding activity, functional antagonism of CCR1 as well as good species cross-reactivity. In addition, compound 22 also showed desirable pharmacokinetic profiles and was selected for in vivo studies in the mouse collagen-induced arthritis model.