Fig. 4. Thiazole compounds do not improve metabolic endpoints after day 2, and BCAA/BCKA rebound occurs over time.

A–C Mice were fed HFD for 10 weeks, at which time animals were randomized into groups, and treated daily with vehicle or PF-07238025 for 9 days (N = 9–10 animals/group; statistics were performed using one-way ANOVA with Tukey HSD test, *p = 0.02). A Study design. B, C An oGTT was performed at day 2. B oGTT. C oGTT AUC. D–N Mice were fed HFD for 10 weeks, at which time animals were randomized into groups, and treated daily with vehicle or PF-07238025 for 8 weeks. D Study design. E, F An oGTT was performed at week 2 (N = 9–10 animals/group). E oGTT, F oGTT AUC. G, H Plasma and livers were isolated 1 h post final compound dose. G Hepatic triglycerides (N = 9–10 animals/group). H Plasma insulin levels (N = 8–10 animals/group). I–N PK/PD assessments were performed on day 1 (I, J) (N = 4 animals/group; statistics were performed by Welch’s t-test), after 7 days (K, L) (N = 4 animals/group; statistics were performed by Welch’s t-test), or 6 weeks (M, N) (N = 4–10 animals/group; statistics were performed using one-way ANOVA with Tukey HSD test) of treatment, in which mice were dosed with compound, and timed bleeds were performed to measure drug levels, BCAA, and BCKA levels. I Day 1 Leucine (***p = 0.0049), (J) Day 1 Ketoleucine (#p = 1.64 × 10⁻⁶, ***p = 0.003). K Day 7 Leucine, (L) Day 7 Ketoleucine (***p = 0.001). M Week 6 Leucine (*p = 0.019), (N) week 6 Ketoleucine (****p < 0.001, ***p = 0.001). Data represent the mean ± SEM. Source data are provided as a Source Data file.