Tag: M.W=350-400

Vetrichelvan, Muthalagu published the artcileDevelopment of a Scalable Synthesis of the Small Molecule TGFβR1 Inhibitor BMS-986260, Product Details of C18H12ClFN6O, the publication is Organic Process Research & Development (2020), 24(7), 1310-1320, database is CAplus.

A scalable route to the small mol. TGFβR1 inhibitor BMS-986260 I was developed. This alternative approach circumvented the purification of intermediates by column chromatog. and provided access to multikilogram quantities of the key intermediate, 6-formylimidazo[1,2-b]pyridazine-3-carbonitrile. The safety aspects of the synthetic approach to the other fragment of the API (TosMIC) were critically evaluated, and a robust process for its large-scale synthesis was successfully demonstrated.

Organic Process Research & Development 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 C10H10O6, Product Details of C18H12ClFN6O.

Referemce:
https://en.wikipedia.org/wiki/Pyridazine,
Pyridazine | C4H4N2 – PubChem

Parrish, Karen E. published the artcilePharmacodynamics-based approach for efficacious human dose projection of BMS-986260, a small molecule transforming growth factor beta receptor 1 inhibitor, HPLC of Formula: 2001559-19-7, the publication is Biopharmaceutics & Drug Disposition (2021), 42(4), 137-149, database is CAplus and MEDLINE.

For decades, tumor biol. implicated TGF-β as an attractive therapeutic target due to its immunosuppressive effects. Toward this end, multiple pharmaceutical companies developed a number of drug modalities that specifically target the TGF-β pathway. BMS-986260 is a small mol., selective TGF-βR1 kinase inhibitor that was under preclin. development for oncol. In vivo studies across mouse, rat, dog, and monkey and cryopreserved hepatocytes predicted human pharmacokinetics (PK) and distribution of BMS-986260. Efficacy studies of BMS-986260 were undertaken in the MC38 murine colon cancer model, and target engagement, as measured by phosphorylation of SMAD2/3, was assessed in whole blood to predict the clin. efficacious dose. The human clearance is predicted to be low, 4.25 mL/min/kg. BMS-986260 provided a durable and robust antitumor response at 3.75 mg/kg daily and 1.88 mg/kg twice-daily dosing regimens. Phosphorylation of SMAD2/3 was 3.5-fold less potent in human monocytes than other preclin. species. Taken together, the projected clin. efficacious dose was 600 mg QD or 210 mg BID for 3 days followed by a 4-day drug holiday. Mechanism-based cardiovascular findings in the rat ultimately led to the termination of BMS-986260. This study describes the preclin. PK characterization and pharmacodynamics-based efficacious dose projection of a novel small mol. TGF-βR1 inhibitor.

Biopharmaceutics & Drug Disposition 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, HPLC of Formula: 2001559-19-7.

Referemce:
https://en.wikipedia.org/wiki/Pyridazine,
Pyridazine | C4H4N2 – PubChem

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

Velaparthi, Upender published the artcileDiscovery of BMS-986260, a Potent, Selective, and Orally Bioavailable TGFβR1 Inhibitor as an Immuno-oncology Agent, SDS of cas: 2001559-19-7, the publication is ACS Medicinal Chemistry Letters (2020), 11(2), 172-178, database is CAplus and MEDLINE.

Novel imidazole-based TGFβR1 inhibitors were identified and optimized for potency, selectivity, and pharmacokinetic and physicochem. characteristics. Herein, we report the discovery, optimization, and evaluation of a potent, selective, and orally bioavailable TGFβR1 inhibitor, 10 (BMS-986260). This compound demonstrated functional activity in multiple TGFβ-dependent cellular assays, excellent kinome selectivity, favorable pharmacokinetic properties, and curative in vivo efficacy in combination with anti-PD-1 antibody in murine colorectal cancer (CRC) models. Since daily dosing of TGFβR1 inhibitors is known to cause class-based cardiovascular (CV) toxicities in preclin. species, a dosing holiday schedule in the anti-PD-1 combination efficacy studies was explored. An intermittent dosing regimen of 3 days on and 4 days off allowed mitigation of CV toxicities in one month dog and rat toxicol. studies and also provided similar efficacy as once daily dosing.

ACS Medicinal Chemistry Letters 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 C9H21NO3, SDS of cas: 2001559-19-7.

Referemce:
https://en.wikipedia.org/wiki/Pyridazine,
Pyridazine | C4H4N2 – PubChem