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Based on ( R )- N -methyl- N -(5-azaspiro[2.4]heptan-7-yl)-7 H -pyrrolo[2,3- d ]pyrimidin-4-amine as a core scaffold, we identified ( R )-3-(7-(methyl(7 H -pyrrolo[2,3- d ]pyrimidin-4-yl)amino)-5-azaspiro[2.4]heptan-5-yl)-3-oxopropanenitrile [ ( R ) - 6c ] as a JAK1 selective inhibitor. The structural design was based on the combination of tofacitinib's 7-deazapurine and 5-azaspiro[2.4]heptan-7-amine. Compound ( R ) - 6c exhibited an IC 50 value of 8.5 nM against JAK1 with a selectivity index of 48 over JAK2. To optimize ( R ) - 6c as a lead compound, we performed in vitro ADME, hERG, kinase profiling, and pharmacokinetic tests. Mouse and rat in vivo studies verified that ( R ) - 6c exhibited desired efficacies in CIA and AIA models.

medchemcomm

Design, synthesis and evaluation of (R)-3-(7-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5-azaspiro[2.4]heptan-5-yl)-3-oxopropanenitrile as a JAK1-selective inhibitor