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

Rajesh Bahekar; Bhushan Dave; Shubhangi Soman; Dipam Patel; Rajendra Chopade; Radhika Funde; Jeevan Kumar; S Sachchidanand; Poonam Giri; Abhijit Chatterjee; Jogeswar Mahapatra; Purvi Vyas; Krishnarup Ghoshdastidar; Debdutta Bandyopadhyay; Ranjit C Desai

doi:10.1016/j.bmcl.2019.04.007

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. Epub 2019 Apr 4.

Authors

Affiliations

¹ Department of Medicinal Chemistry, Zydus Research Centre, Sarkhej-Bavla, N.H. 8A Moraiya, Ahmedabad 382210, India. Electronic address: rajeshbahekar@zyduscadila.com.
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.

MeSH terms

Class I Phosphatidylinositol 3-Kinases / antagonists & inhibitors*
Class I Phosphatidylinositol 3-Kinases / metabolism
Dose-Response Relationship, Drug
Drug Discovery*
Humans
Molecular Structure
Phosphoinositide-3 Kinase Inhibitors / chemical synthesis
Phosphoinositide-3 Kinase Inhibitors / chemistry
Phosphoinositide-3 Kinase Inhibitors / pharmacology*
Quinolones / chemical synthesis
Quinolones / chemistry
Quinolones / pharmacology*
Structure-Activity Relationship

Substances

Phosphoinositide-3 Kinase Inhibitors
Quinolones
Class I Phosphatidylinositol 3-Kinases
PIK3CD protein, human