Rak, Gregory D. published the artcileIntermittent dosing of the transforming growth factor beta receptor 1 inhibitor, BMS-986260, mitigates class-based cardiovascular toxicity in dogs but not rats, COA of Formula: C18H12ClFN6O, the publication is Journal of Applied Toxicology (2020), 40(7), 931-946, database is CAplus and MEDLINE.
Small-mol. inhibitors of transforming growth factor beta receptor 1 (TGFβRI) have a history of significant class-based toxicities (eg, cardiac valvulopathy) in preclin. species that have limited their development as new medicines. Nevertheless, some TGFβRI inhibitors have entered into clin. trials using intermittent-dosing schedules and exposure limits in an attempt to avoid these toxicities. This report describes the toxicity profile of the small-mol. TGFβRI inhibitor, BMS-986260, in rats and dogs. Daily oral dosing for 10 days resulted in valvulopathy and/or aortic pathol. at systemic exposures that would have been targeted clin., preventing further development with this dosing schedule. These toxicities were not observed in either species in 1-mo studies using the same doses on an intermittent-dosing schedule of 3 days on and 4 days off (QDx3 once weekly). Subsequently, 3-mo studies were conducted (QDx3 once weekly), and while there were no cardiovascular findings in dogs, valvulopathy and mortality occurred early in rats. The only difference compared to the 1-mo study was that the rats in the 3-mo study were 2 wk younger at the start of dosing. Therefore, a follow-up 1-mo study was conducted to evaluate whether the age of rats influences sensitivity to target-mediated toxicity. Using the same dosing schedule and similar doses as in the 3-mo study, there was no difference in the toxicity of BMS-986260 in young (8 wk) or adult (8 mo) rats. In summary, an intermittent-dosing schedule mitigated target-based cardiovascular toxicity in dogs but did not prevent valvulopathy in rats, and thus the development of BMS-986260 was terminated.
Journal of Applied Toxicology published new progress about 2001559-19-7. 2001559-19-7 belongs to pyridazine, auxiliary class TGF-beta/Smad,TGF-beta Receptor, name is 6-(4-(3-Chloro-4-fluorophenyl)-1-(2-hydroxyethyl)-1H-imidazol-5-yl)imidazo[1,2-b]pyridazine-3-carbonitrile, and the molecular formula is C18H12ClFN6O, COA of Formula: C18H12ClFN6O.
Referemce:
https://en.wikipedia.org/wiki/Pyridazine,
Pyridazine | C4H4N2 – PubChem