Discovery of 3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one derivatives as novel JAK inhibitors

Hiroaki Yamagishi; Shohei Shirakami; Yutaka Nakajima; Akira Tanaka; Fumie Takahashi; Hisao Hamaguchi; Keiko Hatanaka; Ayako Moritomo; Masamichi Inami; Yasuyuki Higashi; Takayuki Inoue

doi:10.1016/j.bmc.2015.05.028

Discovery of 3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one derivatives as novel JAK inhibitors

Bioorg Med Chem. 2015 Aug 1;23(15):4846-4859. doi: 10.1016/j.bmc.2015.05.028. Epub 2015 May 23.

Affiliations

¹ Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. Electronic address: hiroaki.yamagishi@astellas.com.
² Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
³ Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. Electronic address: inoue_eck@mii.maruho.co.jp.

PMID: 26059596
DOI: 10.1016/j.bmc.2015.05.028

Abstract

Because Janus kinases (JAKs) play a crucial role in cytokine-mediated signal transduction, JAKs are an attractive target for the treatment of organ transplant rejection and autoimmune diseases such as rheumatoid arthritis (RA). To identify JAK inhibitors, we focused on the 1H-pyrrolo[2,3-b]pyridine derivative 3, which exhibited moderate JAK3 and JAK1 inhibitory activities. Optimization of 3 identified the tricyclic imidazo-pyrrolopyridinone derivative 19, which exhibited potent JAK3 and JAK1 inhibitory activities (IC50=1.1 nM, 1.5 nM, respectively) with favorable metabolic stability.

Keywords: Autoimmune diseases; IL-2; Immunomodulator; Janus kinase inhibitor; Organ transplant rejection.

MeSH terms

Animals
Binding Sites
Cell Proliferation / drug effects
Cells, Cultured
Crystallography, X-Ray
Cytochrome P-450 CYP3A / metabolism
Humans
Janus Kinase 1 / antagonists & inhibitors*
Janus Kinase 1 / metabolism
Janus Kinase 2 / antagonists & inhibitors
Janus Kinase 2 / metabolism
Janus Kinase 3 / antagonists & inhibitors*
Janus Kinase 3 / metabolism
Male
Microsomes, Liver / metabolism
Molecular Docking Simulation
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacology
Protein Structure, Tertiary
Pyridines / chemistry
Pyridones / chemical synthesis
Pyridones / chemistry*
Pyridones / pharmacology
Pyrroles / chemistry
Rats
Rats, Inbred Lew
Spleen / cytology
Spleen / drug effects
Spleen / metabolism
Structure-Activity Relationship

Substances

Protein Kinase Inhibitors
Pyridines
Pyridones
Pyrroles
Cytochrome P-450 CYP3A
Janus Kinase 1
Janus Kinase 2
Janus Kinase 3
pyrrolo(2, 3-b)pyridine