Fig. 2

In vivo characterization of a novel synthetic CD38 inhibitor. a Inhibition of the base-exchange activity of recombinant human (rh) or mouse (rm) CD38 protein using the established CD38 inhibitor 78C and the novel inhibitor GSK978A. Sigmoidal dose-response curves were fitted to replicate experiments (n = 12-15). Molecular structures and calculated pIC50 values are indicated. b Stability of 500 nM GSK978A in liver microsomal fractions from selected preclinical species over time. Half-lives (t_0.5) were calculated from linear regressions. N = 3 experiments per species. c Pharmacokinetics of GSK978A in mouse blood after an oral dose of 10 mg/kg. The dashed line indicates approximate IC50 of 12 ng/mL. N = 3 mice. d Intratissue compound exposures 2 h after a range of oral doses of GSK978A. N = 4 mice per dose. WAT, white adipose tissue. e Tissue-specific pharmacodynamics measured as NAD content relative to an internal standard (IS) 2 h after 0-30 mg/kg oral doses of GSK978A. Significance was determined by one-way ANOVA with Tukey’s post hoc test (*p < 0.05, ****p < 0.0001 compared to vehicle controls). f Tissue-specific pharmacodynamics as a function of exposure measured as normalized change in NAD content 2 h after 0-3 mg/kg doses of GSK978A. Lines indicate sigmoidal best-fit regressions approaching the indicated Bmax limits. N = 4 mice per dose. Mice were WT obese males for subpanels c-f. Error bars represent SEM