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Title: Discovery of Clinical Candidate 1-{[(2 S ,3 S ,4 S )-3-Ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide (PF-06650833), a Potent, Selective Inhibitor of Interleukin-1 Receptor Associated Kinase 4 (IRAK4), by Fragment-Based Drug Design

Abstract

Through fragment-based drug design focused on engaging the active site of IRAK4 and leveraging three-dimensional topology in a ligand-efficient manner, a micromolar hit identified from a screen of a Pfizer fragment library was optimized to afford IRAK4 inhibitors with nanomolar potency in cellular assays. The medicinal chemistry effort featured the judicious placement of lipophilicity, informed by co-crystal structures with IRAK4 and optimization of ADME properties to deliver clinical candidate PF-06650833 (compound 40). This compound displays a 5-unit increase in lipophilic efficiency from the fragment hit, excellent kinase selectivity, and pharmacokinetic properties suitable for oral administration.

Authors:
ORCiD logo; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; more »; ; ; ; ; ; ORCiD logo; ; ;  [1]; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ;  [1]; ; « less
  1. Worldwide Medicinal Chemistry, Pfizer Inc., 1070 Science Center Drive, San Diego, California 92121, United States
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
INDUSTRY
OSTI Identifier:
1405007
Resource Type:
Journal Article
Resource Relation:
Journal Name: Journal of Medicinal Chemistry; Journal Volume: 60; Journal Issue: 13
Country of Publication:
United States
Language:
ENGLISH
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; 60 APPLIED LIFE SCIENCES

Citation Formats

Lee, Katherine L., Ambler, Catherine M., Anderson, David R., Boscoe, Brian P., Bree, Andrea G., Brodfuehrer, Joanne I., Chang, Jeanne S., Choi, Chulho, Chung, Seungwon, Curran, Kevin J., Day, Jacqueline E., Dehnhardt, Christoph M., Dower, Ken, Drozda, Susan E., Frisbie, Richard K., Gavrin, Lori K., Goldberg, Joel A., Han, Seungil, Hegen, Martin, Hepworth, David, Hope, Heidi R., Kamtekar, Satwik, Kilty, Iain C., Lee, Arthur, Lin, Lih-Ling, Lovering, Frank E., Lowe, Michael D., Mathias, John P., Morgan, Heidi M., Murphy, Elizabeth A., Papaioannou, Nikolaos, Patny, Akshay, Pierce, Betsy S., Rao, Vikram R., Saiah, Eddine, Samardjiev, Ivan J., Samas, Brian M., Shen, Marina W. H., Shin, Julia H., Soutter, Holly H., Strohbach, Joseph W., Symanowicz, Peter T., Thomason, Jennifer R., Trzupek, John D., Vargas, Richard, Vincent, Fabien, Yan, Jiangli, Zapf, Christoph W., and Wright, Stephen W.. Discovery of Clinical Candidate 1-{[(2 S ,3 S ,4 S )-3-Ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide (PF-06650833), a Potent, Selective Inhibitor of Interleukin-1 Receptor Associated Kinase 4 (IRAK4), by Fragment-Based Drug Design. United States: N. p., 2017. Web. doi:10.1021/acs.jmedchem.7b00231.
Lee, Katherine L., Ambler, Catherine M., Anderson, David R., Boscoe, Brian P., Bree, Andrea G., Brodfuehrer, Joanne I., Chang, Jeanne S., Choi, Chulho, Chung, Seungwon, Curran, Kevin J., Day, Jacqueline E., Dehnhardt, Christoph M., Dower, Ken, Drozda, Susan E., Frisbie, Richard K., Gavrin, Lori K., Goldberg, Joel A., Han, Seungil, Hegen, Martin, Hepworth, David, Hope, Heidi R., Kamtekar, Satwik, Kilty, Iain C., Lee, Arthur, Lin, Lih-Ling, Lovering, Frank E., Lowe, Michael D., Mathias, John P., Morgan, Heidi M., Murphy, Elizabeth A., Papaioannou, Nikolaos, Patny, Akshay, Pierce, Betsy S., Rao, Vikram R., Saiah, Eddine, Samardjiev, Ivan J., Samas, Brian M., Shen, Marina W. H., Shin, Julia H., Soutter, Holly H., Strohbach, Joseph W., Symanowicz, Peter T., Thomason, Jennifer R., Trzupek, John D., Vargas, Richard, Vincent, Fabien, Yan, Jiangli, Zapf, Christoph W., & Wright, Stephen W.. Discovery of Clinical Candidate 1-{[(2 S ,3 S ,4 S )-3-Ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide (PF-06650833), a Potent, Selective Inhibitor of Interleukin-1 Receptor Associated Kinase 4 (IRAK4), by Fragment-Based Drug Design. United States. doi:10.1021/acs.jmedchem.7b00231.
Lee, Katherine L., Ambler, Catherine M., Anderson, David R., Boscoe, Brian P., Bree, Andrea G., Brodfuehrer, Joanne I., Chang, Jeanne S., Choi, Chulho, Chung, Seungwon, Curran, Kevin J., Day, Jacqueline E., Dehnhardt, Christoph M., Dower, Ken, Drozda, Susan E., Frisbie, Richard K., Gavrin, Lori K., Goldberg, Joel A., Han, Seungil, Hegen, Martin, Hepworth, David, Hope, Heidi R., Kamtekar, Satwik, Kilty, Iain C., Lee, Arthur, Lin, Lih-Ling, Lovering, Frank E., Lowe, Michael D., Mathias, John P., Morgan, Heidi M., Murphy, Elizabeth A., Papaioannou, Nikolaos, Patny, Akshay, Pierce, Betsy S., Rao, Vikram R., Saiah, Eddine, Samardjiev, Ivan J., Samas, Brian M., Shen, Marina W. H., Shin, Julia H., Soutter, Holly H., Strohbach, Joseph W., Symanowicz, Peter T., Thomason, Jennifer R., Trzupek, John D., Vargas, Richard, Vincent, Fabien, Yan, Jiangli, Zapf, Christoph W., and Wright, Stephen W.. Mon . "Discovery of Clinical Candidate 1-{[(2 S ,3 S ,4 S )-3-Ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide (PF-06650833), a Potent, Selective Inhibitor of Interleukin-1 Receptor Associated Kinase 4 (IRAK4), by Fragment-Based Drug Design". United States. doi:10.1021/acs.jmedchem.7b00231.
@article{osti_1405007,
title = {Discovery of Clinical Candidate 1-{[(2 S ,3 S ,4 S )-3-Ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide (PF-06650833), a Potent, Selective Inhibitor of Interleukin-1 Receptor Associated Kinase 4 (IRAK4), by Fragment-Based Drug Design},
author = {Lee, Katherine L. and Ambler, Catherine M. and Anderson, David R. and Boscoe, Brian P. and Bree, Andrea G. and Brodfuehrer, Joanne I. and Chang, Jeanne S. and Choi, Chulho and Chung, Seungwon and Curran, Kevin J. and Day, Jacqueline E. and Dehnhardt, Christoph M. and Dower, Ken and Drozda, Susan E. and Frisbie, Richard K. and Gavrin, Lori K. and Goldberg, Joel A. and Han, Seungil and Hegen, Martin and Hepworth, David and Hope, Heidi R. and Kamtekar, Satwik and Kilty, Iain C. and Lee, Arthur and Lin, Lih-Ling and Lovering, Frank E. and Lowe, Michael D. and Mathias, John P. and Morgan, Heidi M. and Murphy, Elizabeth A. and Papaioannou, Nikolaos and Patny, Akshay and Pierce, Betsy S. and Rao, Vikram R. and Saiah, Eddine and Samardjiev, Ivan J. and Samas, Brian M. and Shen, Marina W. H. and Shin, Julia H. and Soutter, Holly H. and Strohbach, Joseph W. and Symanowicz, Peter T. and Thomason, Jennifer R. and Trzupek, John D. and Vargas, Richard and Vincent, Fabien and Yan, Jiangli and Zapf, Christoph W. and Wright, Stephen W.},
abstractNote = {Through fragment-based drug design focused on engaging the active site of IRAK4 and leveraging three-dimensional topology in a ligand-efficient manner, a micromolar hit identified from a screen of a Pfizer fragment library was optimized to afford IRAK4 inhibitors with nanomolar potency in cellular assays. The medicinal chemistry effort featured the judicious placement of lipophilicity, informed by co-crystal structures with IRAK4 and optimization of ADME properties to deliver clinical candidate PF-06650833 (compound 40). This compound displays a 5-unit increase in lipophilic efficiency from the fragment hit, excellent kinase selectivity, and pharmacokinetic properties suitable for oral administration.},
doi = {10.1021/acs.jmedchem.7b00231},
journal = {Journal of Medicinal Chemistry},
number = 13,
volume = 60,
place = {United States},
year = {Mon Mar 27 00:00:00 EDT 2017},
month = {Mon Mar 27 00:00:00 EDT 2017}
}