SR-3306

SR-3306 is a selective, potent, highly brain penetrant JNK inhibitor. IC50 & Target: JNK^[1] In Vitro: The effect of SR-3306 or Tat-Sab on cell viability in response to oxidative stress is measured by an MTT assay. H9c2 cells treated with 100 μM H₂O₂/FeSO₄ are ~40% viable, whereas the addition of 500 nM SR-3306 or 500 nM SR3562 to cells treated with 100 μM H₂O₂/FeSO₄ increases viability to ~90%, and the addition of 10 μM Tat-Sab peptide to cells treated with 100 μM H₂O₂/FeSO₄ increases viability to ~70% compared with 98% viability in untreated cells. Similar results are found for primary human cardiomyocytes ^[2]. In Vivo: Administration of SR-3306 [10 mg/kg/day (s.c.) for 14 days] increases the number of tyrosine hydroxylase immunoreactive (TH⁺) neurons in the SNpc by 6-fold and reduces the loss of the TH⁺ terminals in the striatum relative to the corresponding side of 6-OHDA-lesioned rats that receive only vehicle (p<0.05). In addition, SR-3306 [10 mg/kg/day (s.c.) for 14 days] decreases d-amphetamine-induced circling by 87% compared to 6-hydroxydopamine (6-OHDA)-lesioned animals given vehicle. Steady-state brain levels of SR-3306 at day 14 are 347 nM, which is approximately 2-fold higher than the cell-based IC₅₀ for this compound. Finally, immunohistochemical staining for phospho-c-jun (p-c-jun) reveals that SR-3306 [10 mg/kg/day (s.c.) for 14 days] produces a 2.3-fold reduction of the number of immunoreactive neurons in the substantia nigra pars compacta (SNpc) relative to vehicle treated rats^[1]. In lean mice, intraperitoneal (i.p.) or intracerebroventricular (i.c.v.) administration of SR-3306 reduces food intake and body weight. Moreover, i.p. and i.c.v. administrations of SR11935 exert similar anorectic effects as SR3306, which suggests JNK2 or JNK3 mediates aspect of the anorectic effect by pan-JNK inhibition. Furthermore, daily i.p. injection of SR-3306 (7 days) prevents the increases in food intake and weight gain in lean mice upon high-fat diet feeding, and this injection paradigm reduced high-fat intake and obesity in diet-induced obese (DIO) mice^[3].