2. Academic Validation
  3. Optimisation of momelotinib with improved potency and efficacy as pan-JAK inhibitor

Optimisation of momelotinib with improved potency and efficacy as pan-JAK inhibitor

  • Bioorg Med Chem Lett. 2022 Jun 15;66:128728. doi: 10.1016/j.bmcl.2022.128728.
Jigar Desai 1,  Bhaumin Patel 2,  Archana Gite 2,  Nandini Panchal 2,  Sanjay Gite 2,  Anil Argade 2,  Jeevan Kumar 2,  S Sachchidanand 2,  Debdutta Bandyopadhyay 2,  Krishnarup Ghoshdastidar 2,  Hoshang Patel 2,  Abhijit Chatterjee 2,  Jogeshwar Mahapatra 2,  Manoranjan Sharma 2,  Poonam Giri 2,  Sanjay Kumar 2,  Mukul Jain 2,  Rajiv Sharma 2,  Ranjit Desai 2
Affiliations

Affiliations

  • 1 Zydus Research Centre, Cadila Healthcare Ltd, Sarkhej-Bavla N.H. No. 8A, Moraiya, Ahmedabad 382210, India. Electronic address: [email protected].
  • 2 Zydus Research Centre, Cadila Healthcare Ltd, Sarkhej-Bavla N.H. No. 8A, Moraiya, Ahmedabad 382210, India.
PMID: 35413417 DOI: 10.1016/j.bmcl.2022.128728
Abstract

Dysregulated JAK-STAT signaling has been proven to be involved in several immune-mediated diseases. Several janus kinase (JAK) inhibitors have been approved for the treatment of various inflammatory and autoimmune diseases such as rheumatoid arthritis (RA), plaque psoriasis, psoriatic arthritis, inflammatory bowel disease (IBD). Here, we report the design, optimisation, synthesis and biological evaluation of momelotinib analogues (a pyrimidine based JAK Inhibitor), to get pan-JAK inhibitors. Systematic structure activity relationship studies led to the discovery of compound 32, which potently inhibited JAK1, JAK2 and JAK3. The in vivo investigation indicated that compound 32 possessed favourable pharmacokinetic properties and displayed superior anti-inflammatory efficacy than momelotinib 1. Accordingly, compound 32 was advanced into preclinical development.

Keywords

Inflammation; JAK inhibitor; Momelotinib; Pyrimidine.

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