2. Academic Validation
  3. Discovery of 1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-ones based novel, potent and PI3Kδ selective inhibitors

Discovery of 1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-ones based novel, potent and PI3Kδ selective inhibitors

  • Bioorg Med Chem Lett. 2019 Jun 1;29(11):1313-1319. doi: 10.1016/j.bmcl.2019.04.007.
Rajesh Bahekar 1,  Bhushan Dave 2,  Shubhangi Soman 3,  Dipam Patel 4,  Rajendra Chopade 4,  Radhika Funde 4,  Jeevan Kumar 5,  S Sachchidanand 5,  Poonam Giri 6,  Abhijit Chatterjee 6,  Jogeswar Mahapatra 6,  Purvi Vyas 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: 30975623 DOI: 10.1016/j.bmcl.2019.04.007
Abstract

PI3Kδ is implicated in various inflammatory and autoimmune diseases. For the effective treatment of chronic immunological disorders such as rheumatoid arthritis, it is essential to develop isoform selective PI3Kδ inhibitors. Structure guided optimization of an imidazo-quinolinones based pan-PI3K/m-TOR inhibitor (Dactolisib) led to the discovery of a potent and orally bioavailable PI3Kδ isoform selective inhibitor (10h), with an improved efficacy in the animal models.

Keywords

Design; Imidazo-quinolinones; Inflammatory and autoimmune diseases; PI3K inhibitors; Rheumatoid arthritis; Synthesis and biological study.

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