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
| Autor: | Philip S. Low, Mohamed S. A. Elsayed, Jeongho Park, Sungtae Park, Chang H. Kim, Jeffery J Nielsen, Yves Pommier, Qingyang Liu, Mark Cushman, Keli Agama |
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| Rok vydání: | 2018 |
| Předmět: |
Models
Molecular 0301 basic medicine Protein Conformation Stereochemistry Azetidine 010402 general chemistry 01 natural sciences Catalysis Permeability Article 03 medical and health sciences chemistry.chemical_compound In vivo Drug Discovery Humans Janus Kinase Inhibitors Pyrroles Tissue Distribution Kinome IC50 Janus Kinases Drug discovery 0104 chemical sciences 030104 developmental biology chemistry Tyrosine kinase 2 Molecular Medicine Caco-2 Cells Janus kinase Selectivity Palladium |
| Zdroj: | J Med Chem |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.8b00510 |
| Popis: | 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 (IC(50) = 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. |
| Databáze: | OpenAIRE |
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