Discovery of a JAK1/3 Inhibitor and Use of a Prodrug To Demonstrate Efficacy in a Model of Rheumatoid Arthritis
Steven H. Spergel
1
,
Michael E Mertzman
1
,
James Kempson
1
,
Junqing Guo
1
,
Sylwia Stachura
1
,
Lauren Haque
1
,
Jonathan S. Lippy
1
,
Rosemary F Zhang
1
,
Michael Galella
1
,
Sidney Pitt
1
,
Guoxiang Shen
1
,
Aberra Fura
1
,
Kathleen Gillooly
1
,
Kim W. McIntyre
1
,
Vicky Tang
1
,
John S. Tokarski
1
,
J. S. Sack
1
,
Javed M. Khan
1
,
Percy H. Carter
1
,
Joel C. Barrish
1
,
Steven G. Nadler
1
,
Luisa Salter-Cid
1
,
Gary L. Schieven
1
,
Stephen Wrobleski
1
,
William J. Pitts
1
Publication type: Journal Article
Publication date: 2019-02-13
scimago Q1
wos Q2
SJR: 0.805
CiteScore: 5.8
Impact factor: 4.0
ISSN: 19485875
PubMed ID:
30891131
Organic Chemistry
Drug Discovery
Biochemistry
Abstract
The four members of the Janus family of nonreceptor tyrosine kinases play a significant role in immune function. The JAK family kinase inhibitor, tofacitinib 1, has been approved in the United States for use in rheumatoid arthritis (RA) patients. A number of JAK inhibitors with a variety of JAK family selectivity profiles are currently in clinical trials. Our goal was to identify inhibitors that were functionally selective for JAK1 and JAK3. Compound 22 was prepared with the desired functional selectivity profile, but it suffered from poor absorption related to physical properties. Use of the phosphate prodrug 32 enabled progression to a murine collagen induced arthritis (CIA) model. The demonstration of a robust efficacy in the CIA model suggests that use of phosphate prodrugs may resolve issues with progressing this chemotype for the treatment of autoimmune diseases such as RA.
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Total citations:
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Citations from 2025:
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Spergel S. H. et al. Discovery of a JAK1/3 Inhibitor and Use of a Prodrug To Demonstrate Efficacy in a Model of Rheumatoid Arthritis // ACS Medicinal Chemistry Letters. 2019. Vol. 10. No. 3. pp. 306-311.
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Spergel S. H., Mertzman M. E., Kempson J., Guo J., Stachura S., Haque L., Lippy J. S., Zhang R. F., Galella M., Pitt S., Shen G., Fura A., Gillooly K., McIntyre K. W., Tang V., Tokarski J. S., Sack J. S., Khan J. M., Carter P. H., Barrish J. C., Nadler S. G., Salter-Cid L., Schieven G. L., Wrobleski S., Pitts W. J. Discovery of a JAK1/3 Inhibitor and Use of a Prodrug To Demonstrate Efficacy in a Model of Rheumatoid Arthritis // ACS Medicinal Chemistry Letters. 2019. Vol. 10. No. 3. pp. 306-311.
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TY - JOUR
DO - 10.1021/acsmedchemlett.8b00508
UR - https://doi.org/10.1021/acsmedchemlett.8b00508
TI - Discovery of a JAK1/3 Inhibitor and Use of a Prodrug To Demonstrate Efficacy in a Model of Rheumatoid Arthritis
T2 - ACS Medicinal Chemistry Letters
AU - Spergel, Steven H.
AU - Mertzman, Michael E
AU - Kempson, James
AU - Guo, Junqing
AU - Stachura, Sylwia
AU - Haque, Lauren
AU - Lippy, Jonathan S.
AU - Zhang, Rosemary F
AU - Galella, Michael
AU - Pitt, Sidney
AU - Shen, Guoxiang
AU - Fura, Aberra
AU - Gillooly, Kathleen
AU - McIntyre, Kim W.
AU - Tang, Vicky
AU - Tokarski, John S.
AU - Sack, J. S.
AU - Khan, Javed M.
AU - Carter, Percy H.
AU - Barrish, Joel C.
AU - Nadler, Steven G.
AU - Salter-Cid, Luisa
AU - Schieven, Gary L.
AU - Wrobleski, Stephen
AU - Pitts, William J.
PY - 2019
DA - 2019/02/13
PB - American Chemical Society (ACS)
SP - 306-311
IS - 3
VL - 10
PMID - 30891131
SN - 1948-5875
ER -
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@article{2019_Spergel,
author = {Steven H. Spergel and Michael E Mertzman and James Kempson and Junqing Guo and Sylwia Stachura and Lauren Haque and Jonathan S. Lippy and Rosemary F Zhang and Michael Galella and Sidney Pitt and Guoxiang Shen and Aberra Fura and Kathleen Gillooly and Kim W. McIntyre and Vicky Tang and John S. Tokarski and J. S. Sack and Javed M. Khan and Percy H. Carter and Joel C. Barrish and Steven G. Nadler and Luisa Salter-Cid and Gary L. Schieven and Stephen Wrobleski and William J. Pitts},
title = {Discovery of a JAK1/3 Inhibitor and Use of a Prodrug To Demonstrate Efficacy in a Model of Rheumatoid Arthritis},
journal = {ACS Medicinal Chemistry Letters},
year = {2019},
volume = {10},
publisher = {American Chemical Society (ACS)},
month = {feb},
url = {https://doi.org/10.1021/acsmedchemlett.8b00508},
number = {3},
pages = {306--311},
doi = {10.1021/acsmedchemlett.8b00508}
}
Cite this
MLA
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Spergel, Steven H., et al. “Discovery of a JAK1/3 Inhibitor and Use of a Prodrug To Demonstrate Efficacy in a Model of Rheumatoid Arthritis.” ACS Medicinal Chemistry Letters, vol. 10, no. 3, Feb. 2019, pp. 306-311. https://doi.org/10.1021/acsmedchemlett.8b00508.