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 |
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Authors: | Chieyeon Chough Misuk Joung Sunmin Lee Jaemin Lee Jong Hoon Kim B. Moon Kim |
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Affiliation: | 1. Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 08876, South Korea;2. Yang Ji Chemical Co., Ltd., Gyeonggi Bio-Center, Suwon, Gyeonggi-do 16229, South Korea;3. Han Wha Pharma Co., Ltd., 109, Yagam-gil, Nam-myeon, Chuncheon, Gangwon-do 24468, South Korea |
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Abstract: | 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. |
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Keywords: | JAK inhibitor Rheumatoid arthritis JAK1-selective Collagen-induced arthritis mouse model Adjuvant-induced arthritis rat model |
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