Application of Sequential Palladium Catalysis for the Discovery of Janus Kinase Inhibitors in the Benzo[c]pyrrolo[2,3‑h][1,6]naphthyridin-5-one (BPN) Series

The present account describes the discovery and development of a new benzo­[c]­pyrrolo­[2,3-h]­[1,6]­naphthyridin-5-one (BPN) JAK inhibitory chemotype that has produced selective JAK inhibitors. Sequential palladium chemistry was optimized for the rapid access to a focused library of derivatives to...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2018-12, Vol.61 (23), p.10440-10462
Main Authors: Elsayed, Mohamed S. A, Nielsen, Jeffery J, Park, Sungtae, Park, Jeongho, Liu, Qingyang, Kim, Chang H, Pommier, Yves, Agama, Keli, Low, Philip S, Cushman, Mark
Format: Article
Language:English
Subjects:
Caco-2 Cells
Catalysis
Drug Discovery
Humans
Janus Kinase Inhibitors - chemistry
Janus Kinase Inhibitors - metabolism
Janus Kinase Inhibitors - pharmacokinetics
Janus Kinase Inhibitors - pharmacology
Janus Kinases - chemistry
Janus Kinases - metabolism
Models, Molecular
Palladium - chemistry
Permeability
Protein Conformation
Pyrroles - chemistry
Pyrroles - metabolism
Pyrroles - pharmacokinetics
Pyrroles - pharmacology
Tissue Distribution
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Summary:The present account describes the discovery and development of a new benzo­[c]­pyrrolo­[2,3-h]­[1,6]­naphthyridin-5-one (BPN) JAK inhibitory chemotype that has produced selective JAK inhibitors. Sequential palladium chemistry was optimized for the rapid access to a focused library of derivatives to explore the structure–activity relationships of the new scaffold. Several compounds from the series displayed potencies in the low nanomolar range against the four members of the JAK family with various selectivity profiles. Compound 20a, with an azetidine amide side chain, showed the best selectivity for JAK1 kinase vs JAK2, JAK3, and TYK2, with low nanomolar potency (IC50 = 3.4 nM). On the other hand, BPNs 17b and 18 had good general activity against the JAK family with excellent kinome selectivity profiles. Many of the new BPNs inhibited JAK3-mediated STAT-5 phosphorylation, the production of inflammatory cytokines, and the proliferation of primary T cells. Moreover, BPN 17b showed very similar in vivo results to tofacitinib in a rheumatoid arthritis animal model.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.8b00510