ACS Medicinal Chemistry Letters最新文献

Stabilization of cereblon (CRBN)/neosubstrate complexes with molecular glues followed by degradation of those neosubstrates is an emerging strategy in drug discovery with compelling potential to target certain proteins that were previously considered to be undruggable. In this context, the discovery of novel CRBN ligands is an important area of ongoing research that holds promise to expand the scope of proteins that can be targeted through this mode of action. Herein, we describe the synthesis and evaluation of CRBN ligands featuring heteroaryl glutarimide and dihydrouracil scaffolds. We identified a subset of heteroaryl glutarimides exhibiting potent CRBN binding and increased chemical stability in cell culture media compared with traditional immunomodulatory drugs (IMiDs). This indicates that the scaffolds described herein could become useful starting points for the discovery of novel molecular glue degraders.

Stabilization of cereblon (CRBN)/neosubstrate complexes with molecular glues followed by degradation of those neosubstrates is an emerging strategy in drug discovery with compelling potential to target certain proteins that were previously considered to be undruggable. In this context, the discovery of novel CRBN ligands is an important area of ongoing research that holds promise to expand the scope of proteins that can be targeted through this mode of action. Herein, we describe the synthesis and evaluation of CRBN ligands featuring heteroaryl glutarimide and dihydrouracil scaffolds. We identified a subset of heteroaryl glutarimides exhibiting potent CRBN binding and increased chemical stability in cell culture media compared with traditional immunomodulatory drugs (IMiDs). This indicates that the scaffolds described herein could become useful starting points for the discovery of novel molecular glue degraders.

Provided herein are novel pyrrolidines as main protease inhibitors, pharmaceutical compositions, use of such compounds in treating viral infections, in particular, coronavirus infections, and processes for preparing such compounds.

Provided herein are novel pyrrolidinone urea compounds as FPR2 agonists, pharmaceutical compositions, use of such compounds in treating atherosclerosis and heart failure, and processes for preparing such compounds.

Provided herein are novel aryl hydrocarbon receptor agonists, pharmaceutical compositions, use of such compounds in treating immune-mediated diseases, in particular psoriasis and atopic dermatitis, and processes for preparing such compounds.

Provided herein are novel GIPR antagonists, pharmaceutical compositions, use of such compounds in treating obesity and type 2 diabetes mellitus and processes for preparing such compounds.

Provided herein are novel aryl hydrocarbon receptor agonists, pharmaceutical compositions, use of such compounds in treating immune-mediated diseases, in particular psoriasis and atopic dermatitis, and processes for preparing such compounds.

Provided herein are novel pyrrolidinone urea compounds as FPR2 agonists, pharmaceutical compositions, use of such compounds in treating atherosclerosis and heart failure, and processes for preparing such compounds.

Provided herein are novel GIPR antagonists, pharmaceutical compositions, use of such compounds in treating obesity and type 2 diabetes mellitus and processes for preparing such compounds.