Discovery of diaminopyrimidine-carboxamide derivatives as JAK3 inhibitors
| Autor: | Debdutta Bandyopadhyay, Jigar Desai, Abhijit Chatterjee, Hoshang Patel, S. Sachchidanand, Rajesh Bahekar, Jeevan Kumar, Dipam Patel, Krishnarup Ghoshdastidar, Anil Argade, Harilal Patel, Archana Gite, Bhaumin Patel, Sanjay Gite, Jogeswar Mahapatra, Nandini Panchal, Rajesh Sundar, Ranjit C. Desai, Shubhangi S. Soman |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Male
Pyrimidine medicine.drug_class Carboxamide Pharmacology 01 natural sciences Biochemistry Cell Line Mice Structure-Activity Relationship chemistry.chemical_compound Drug Discovery medicine Animals Humans Cerdulatinib Protein Kinase Inhibitors Molecular Biology Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Chemistry Organic Chemistry Janus Kinase 3 medicine.disease Arthritis Experimental Acute toxicity Rats 0104 chemical sciences Bioavailability Mice Inbred C57BL Molecular Docking Simulation 010404 medicinal & biomolecular chemistry Pyrimidines Diaminopyrimidine Mice Inbred DBA Antirheumatic Agents Rheumatoid arthritis Janus kinase |
| Zdroj: | Bioorganic Chemistry. 99:103851 |
| ISSN: | 0045-2068 |
| DOI: | 10.1016/j.bioorg.2020.103851 |
| Popis: | Selective inhibition of janus kinase (JAK) has been identified as an important strategy for the treatment of autoimmune disorders. Optimization at the C2 and C4-positions of pyrimidine ring of Cerdulatinib led to the discovery of a potent and orally bioavailable 2,4-diaminopyrimidine-5-carboxamide based JAK3 selective inhibitor (11i). A cellular selectivity study further confirmed that 11i preferentially inhibits JAK3 over JAK1, in JAK/STAT signaling pathway. Compound 11i showed good anti-arthritic activity, which could be correlated with its improved oral bioavailability. In the repeat dose acute toxicity study, 11i showed no adverse changes related to gross pathology and clinical signs, indicating that the new class JAK3 selective inhibitor could be viable therapeutic option for the treatment of rheumatoid arthritis. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect