Discovery of diaminopyrimidine-carboxamide derivatives as JAK3 inhibitors

• Published in: Bioorganic chemistry Vol. 99; pp. 103851 - 103864
• Main Authors: Bahekar, Rajesh, Panchal, Nandini, Soman, Shubhangi, Desai, Jigar, Patel, Dipam, Argade, Anil, Gite, Archana, Gite, Sanjay, Patel, Bhaumin, Kumar, Jeevan, S, Sachchidanand, Patel, Harilal, Sundar, Rajesh, Chatterjee, Abhijit, Mahapatra, Jogeswar, Patel, Hoshang, Ghoshdastidar, Krishnarup, Bandyopadhyay, Debdutta, Desai, Ranjit C.
• Format: Journal Article
• Language: English
• Published: SAN DIEGO Elsevier Inc 01.06.2020; Elsevier
• Subjects: Animals; Antirheumatic Agents - chemical synthesis; Antirheumatic Agents - chemistry; Antirheumatic Agents - pharmacology; Arthritis, Experimental - blood; Arthritis, Experimental - drug therapy; Biochemistry & Molecular Biology; Cell Line; Chemistry; Chemistry, Organic; Dose-Response Relationship, Drug; Drug Discovery; Humans; Janus Kinase 3 - antagonists & inhibitors; Janus Kinase 3 - blood; Janus Kinase 3 - metabolism; Life Sciences & Biomedicine; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Molecular Docking Simulation; Molecular Structure; Physical Sciences; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Rats; Science & Technology; Structure-Activity Relationship; POTENT; DESIGN; EFFICACY; MODELS; SELECTIVE INHIBITORS; OPEN-LABEL; ARTHRITIS; SUFFICIENT
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2020.103851

[Display omitted] •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 in vivo anti-arthritic activity and safety profile.•Indicates that the new class JAK3 selective inhibitor could be viable therapeutic option for the treatment of RA. 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.