Open AccessApplication 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
Author(s) -
Mohamed S.A. Elsayed,
Jeffery J Nielsen,
Sungtae Park,
Jeong-Ho Park,
Qingyang Liu,
Chang H. Kim,
Yves Pommier,
Keli Agama,
Philip S. Low,
Mark Cushman
Publication year - 2018
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.8b00510
Subject(s) - chemistry , kinome , tyrosine kinase 2 , janus kinase , selectivity , drug discovery , janus kinase 3 , structure–activity relationship , stereochemistry , amide , azetidine , in vivo , combinatorial chemistry , kinase , in vitro , biochemistry , catalysis , receptor , platelet derived growth factor receptor , microbiology and biotechnology , cytotoxic t cell , antigen presenting cell , growth factor , biology
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.