2. Academic Validation
  3. Discovery of diaminopyrimidine-carboxamide derivatives as JAK3 inhibitors

Discovery of diaminopyrimidine-carboxamide derivatives as JAK3 inhibitors

  • Bioorg Chem. 2020 Jun;99:103851. doi: 10.1016/j.bioorg.2020.103851.
Rajesh Bahekar 1,  Nandini Panchal 2,  Shubhangi Soman 3,  Jigar Desai 4,  Dipam Patel 4,  Anil Argade 4,  Archana Gite 4,  Sanjay Gite 4,  Bhaumin Patel 4,  Jeevan Kumar 5,  Sachchidanand S 5,  Harilal Patel 6,  Rajesh Sundar 6,  Abhijit Chatterjee 6,  Jogeswar Mahapatra 6,  Hoshang Patel 7,  Krishnarup Ghoshdastidar 7,  Debdutta Bandyopadhyay 7,  Ranjit C Desai 4
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Zydus Research Centre, Sarkhej-Bavla, N.H. 8A Moraiya, Ahmedabad 382210, India. Electronic address: [email protected].
  • 2 Department of Medicinal Chemistry, Zydus Research Centre, Sarkhej-Bavla, N.H. 8A Moraiya, Ahmedabad 382210, India; Department of Chemistry, Faculty of Science, M.S. University of Baroda, Vadodara 390002, India.
  • 3 Department of Chemistry, Faculty of Science, M.S. University of Baroda, Vadodara 390002, India.
  • 4 Department of Medicinal Chemistry, Zydus Research Centre, Sarkhej-Bavla, N.H. 8A Moraiya, Ahmedabad 382210, India.
  • 5 Department of Bioinformatics, Zydus Research Centre, Sarkhej-Bavla, N.H. 8A Moraiya, Ahmedabad 382210, India.
  • 6 Department of Pharmacology, Zydus Research Centre, Sarkhej-Bavla, N.H. 8A Moraiya, Ahmedabad 382210, India.
  • 7 Department of Cell Biology, Zydus Research Centre, Sarkhej-Bavla, N.H. 8A Moraiya, Ahmedabad 382210, India.
PMID: 32334196 DOI: 10.1016/j.bioorg.2020.103851
Abstract

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.

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