Development of selective inhibitors for the treatment of rheumatoid arthritis: (R)-3-(3-(Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)-3-oxopropanenitrile as a JAK1-selective inhibitor

Add time:08/27/2019    Source:sciencedirect.com

A series of 3(R)-aminopyrrolidine derivatives were designed and synthesized for JAK1-selective inhibitors through the modification of tofacitinib’s core structure, (3R,4R)-3-amino-4-methylpiperidine. From the new core structures, we selected (R)-N-methyl-N-(pyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine as a scaffold for further SAR studies. From biochemical enzyme assays and liver microsomal stability tests, (R)-3-(3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)-3-oxopropanenitrile (6) was chosen for further in vivo test through oral administration. Compound 6 showed improved selectivity for JAK1 compared to that of tofacitinib (IC50 11, 2.4 × 102, 2.8 × 103, and 1.1 × 102 nM for JAK1, JAK2, JAK3, and TYK2, respectively). In CIA and AIA model tests, compound 6 exhibited similar efficacy to tofacitinib citrate.

We also recommend Trading Suppliers and Manufacturers of C-(1-METHYL-PYRROLIDIN-3-YL)-METHYLAMINE (cas 13005-11-3). Pls Click Website Link as below: cas 13005-11-3 suppliers

Prev:Original ArticlePotential target-related proteins in rabbit platelets treated with active monomers dehydrocorydaline and canadine from Rhizoma corydalis
Next:Research paperDesign, synthesis and biological activity of new amides derived from 3-methyl-3-phenyl-2,5-dioxo-pyrrolidin-1-yl-acetic acid)