4ivd Citations

Identification of C-2 Hydroxyethyl Imidazopyrrolopyridines as Potent JAK1 Inhibitors with Favorable Physicochemical Properties and High Selectivity over JAK2.


Herein we report on the structure-based discovery of a C-2 hydroxyethyl moiety which provided consistently high levels of selectivity for JAK1 over JAK2 to the imidazopyrrolopyridine series of JAK1 inhibitors. X-ray structures of a C-2 hydroxyethyl analog in complex with both JAK1 and JAK2 revealed differential ligand/protein interactions between the two isoforms, and offered an explanation for the observed selectivity. Analysis of historical data from related molecules was used to develop a set of physicochemical compound design parameters to impart desirable properties such as acceptable membrane permeability, potent whole blood activity, and a high degree of metabolic stability. This work culminated in the identification of a highly JAK1 selective compound (31) exhibiting favorable oral bioavailability across a range of preclinical species and robust efficacy in a rat CIA model.

Reviews citing this publication (5)

  1. Progress toward JAK1-selective inhibitors. Menet CJ, Mammoliti O, López-Ramos M. Future Med Chem 7 203-235 (2015)
  2. Evaluation of WO-2013040863, WO-2013041042 and WO-2013043962. Selective JAK1 inhibitors based on a 3-aminopyrazole-4-carboxamide scaffold. Norman P. Expert Opin Ther Pat 24 231-237 (2014)
  3. Advances in kinase inhibition: treating rheumatic diseases and beyond. Gadina M. Curr Opin Rheumatol 26 237-243 (2014)
  4. Selective JAK inhibitors in development for rheumatoid arthritis. Norman P. Expert Opin Investig Drugs 23 1067-1077 (2014)
  5. Selective JAK inhibitors. Dymock BW, Yang EG, Chu-Farseeva Y, Yao L. Future Med Chem 6 1439-1471 (2014)

Articles citing this publication (7)

  1. Discovery of selective and noncovalent diaminopyrimidine-based inhibitors of epidermal growth factor receptor containing the T790M resistance mutation. Hanan EJ, Eigenbrot C, Bryan MC, Burdick DJ, Chan BK, Chen Y, Dotson J, Heald RA, Jackson PS, La H, Lainchbury MD, Malek S, Purkey HE, Schaefer G, Schmidt S, Seward EM, Sideris S, Tam C, Wang S, Yeap SK, Yen I, Yin J, Yu C, Zilberleyb I, Heffron TP. J. Med. Chem. 57 10176-10191 (2014)
  2. Design and synthesis of tricyclic JAK3 inhibitors with picomolar affinities as novel molecular probes. Gehringer M, Pfaffenrot E, Bauer S, Laufer SA. ChemMedChem 9 277-281 (2014)
  3. A probabilistic method to report predictions from a human liver microsomes stability QSAR model: a practical tool for drug discovery. Aliagas I, Gobbi A, Heffron T, Lee ML, Ortwine DF, Zak M, Khojasteh SC. J. Comput. Aided Mol. Des. 29 327-338 (2015)
  4. Discovery of 3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one derivatives as novel JAK inhibitors. Yamagishi H, Shirakami S, Nakajima Y, Tanaka A, Takahashi F, Hamaguchi H, Hatanaka K, Moritomo A, Inami M, Higashi Y, Inoue T. Bioorg. Med. Chem. 23 4846-4859 (2015)
  5. Enhancing specificity in the Janus kinases: a study on the thienopyridine JAK2 selective mechanism combined molecular dynamics simulation. Li JJ, Cheng P, Tu J, Zhai HL, Zhang XY. Mol Biosyst 12 575-587 (2016)
  6. Ensemble docking-based virtual screening yields novel spirocyclic JAK1 inhibitors. Bajusz D, Ferenczy GG, Keserű GM. J. Mol. Graph. Model. 70 275-283 (2016)
  7. 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)