4i5c Citations

Novel triazolo-pyrrolopyridines as inhibitors of Janus kinase 1.


The identification of a novel fused triazolo-pyrrolopyridine scaffold, optimized derivatives of which display nanomolar inhibition of Janus kinase 1, is described. Prototypical example 3 demonstrated lower cell potency shift, better permeability in cells and higher oral exposure in rat than the corresponding, previously reported, imidazo-pyrrolopyridine analogue 2. Examples 6, 7 and 18 were subsequently identified from an optimization campaign and demonstrated modest selectivity over JAK2, moderate to good oral bioavailability in rat with overall pharmacokinetic profiles comparable to that reported for an approved pan-JAK inhibitor (tofacitinib).

Reviews citing this publication (3)

  1. Progress toward JAK1-selective inhibitors. Menet CJ, Mammoliti O, López-Ramos M. Future Med Chem 7 203-235 (2015)
  2. Selective JAK inhibitors in development for rheumatoid arthritis. Norman P. Expert Opin Investig Drugs 23 1067-1077 (2014)
  3. Selective JAK inhibitors. Dymock BW, Yang EG, Chu-Farseeva Y, Yao L. Future Med Chem 6 1439-1471 (2014)

Articles citing this publication (6)

  1. Synthesis and evaluation of anti-tubercular activity of 6-(4-substitutedpiperazin-1-yl) phenanthridine analogues. Nagesh HN, Suresh N, Mahalakshmi Naidu K, Arun B, Padma Sridevi J, Sriram D, Yogeeswari P, Chandra Sekhar KV. Eur J Med Chem 74 333-339 (2014)
  2. Anilino-monoindolylmaleimides as potent and selective JAK3 inhibitors. McDonnell ME, Bian H, Wrobel J, Smith GR, Liang S, Ma H, Reitz AB. Bioorg. Med. Chem. Lett. 24 1116-1121 (2014)
  3. Scaffold hopping towards potent and selective JAK3 inhibitors: discovery of novel C-5 substituted pyrrolopyrazines. de Vicente J, Lemoine R, Bartlett M, Hermann JC, Hekmat-Nejad M, Henningsen R, Jin S, Kuglstatter A, Li H, Lovey AJ, Menke J, Niu L, Patel V, Petersen A, Setti L, Shao A, Tivitmahaisoon P, Vu MD, Soth M. Bioorg. Med. Chem. Lett. 24 4969-4975 (2014)
  4. Artocarpus altilis CG-901 alters critical nodes in the JH1-kinase domain of Janus kinase 2 affecting upstream JAK/STAT3 signaling. Nash O, Omotuyi O, Lee J, Kwon BM, Ogbadu L. J Mol Model 21 280 (2015)
  5. Ensemble docking-based virtual screening yields novel spirocyclic JAK1 inhibitors. Bajusz D, Ferenczy GG, Keserű GM. J. Mol. Graph. Model. 70 275-283 (2016)
  6. Molecular modeling-driven approach for identification of Janus kinase 1 inhibitors through 3D-QSAR, docking and molecular dynamics simulations. Itteboina R, Ballu S, Sivan SK, Manga V. J. Recept. Signal Transduct. Res. 37 453-469 (2017)