To guide our initial SAR exploration work, we obtained liver microsomal intrinsic clearance data for five of the initial 18 compounds assayed by CO-ADD (Supplementary Information -CDCO Report and Supplementary Information -Biology). We then acquired intrinsic clearance, plasma protein binding, and solubility data on further compounds throughout the SAR campaign (Tables and, Supplementary Information -Biology). Our target was to identify compounds with promising characteristics for lead development: MIC < 4 µg/mL, aqueous solubility ≥ 10 μM, Chrom Log D7.4 values below 2, mouse liver CLint < 9.0 µL/min/mg protein, rat hepatocyte CLint < 5 µL/min/10 6 cells and human plasma protein binding (PPB) ≤ 95%. The data for selected compounds (full data are available in the Supplementary Information) show that these compounds have moderate to high intrinsic clearance (Figure ). The more polar compounds (lower LogD) had reduced PPB and were more metabolically stable. In general, potency was negatively correlated with polarity and solubility, in that the most potent compounds were poorly soluble. Of the initially-studied compounds, the potent benzofuran 821 performed better than the potent benzothiophene 822 (particularly in rat liver microsomes) though it is also known that benzofuran-containing compounds can undergo metabolic activation at the 2-position 18b which had made replacement of this functionality a priority for series development. We also confirmed potential sites of metabolism using SMARTCyp (, Figure in Supporting Information -Biology).