Design, synthesis and evaluation of substituted N-methyl-N-(pyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amines as JAK1-selective inhibitors for the treatment of rheumatoid arthritis
류마티스 관절염 치료를 위한 JAK1 선택적 억제제로서의 N-메틸-N-(피롤리딘-3-일)-7H-피롤로[2,3-d]피리미딘-4-아민의 설계, 합성 및 평가
- 자연과학대학 화학부
- Issue Date
- 서울대학교 대학원
- JAK inhibitor ; rheumatoid arthritis ; JAK1-selective ; collagen-induced arthritis mouse model ; adjuvant-induced arthritis rat model
- 학위논문 (박사)-- 서울대학교 대학원 : 자연과학대학 화학부, 2018. 2. 김병문.
- Based on (R)-N-methyl-N-(5-azaspiro[2.4]heptan-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine as a core scaffold, we identified (R)-3-(7-(methyl(7H-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 tofacitinibs 7-deazapurine and 5-azaspiro[2.4]heptan-7-amine. Compound (R)-6c exhibited 8.5 nM IC50 on JAK1 with a selectivity index of 48 over JAK2. To optimize (R)-6c as a lead compound, we performed cell-based functional assays, human whole blood tests, in vitro ADME, hERG, kinase profiling, and pharmacokinetic tests. Rat in vivo studies verified that (R)-6c exhibited desired efficacies on CIA and AIA models.