Discovery of GS-9973, a Selective and Orally Efficacious Inhibitor of Spleen Tyrosine Kinase
Spleen tyrosine kinase (Syk) is an attractive drug target in autoimmune, inflammatory, and oncology disease indications. The most advanced Syk inhibitor, R406, 1 (or its prodrug form fostamatinib, 2), has shown efficacy in multiple therapeutic indications, but its clinical progress has been hampered...
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| Published in | Journal of medicinal chemistry Vol. 57; no. 9; pp. 3856 - 3873 |
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| Main Authors | , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
WASHINGTON
American Chemical Society
08.05.2014
Amer Chemical Soc |
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| Online Access | Get full text |
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| Abstract | Spleen tyrosine kinase (Syk) is an attractive drug target in autoimmune, inflammatory, and oncology disease indications. The most advanced Syk inhibitor, R406, 1 (or its prodrug form fostamatinib, 2), has shown efficacy in multiple therapeutic indications, but its clinical progress has been hampered by dose-limiting adverse effects that have been attributed, at least in part, to the off-target activities of 1. It is expected that a more selective Syk inhibitor would provide a greater therapeutic window. Herein we report the discovery and optimization of a novel series of imidazo[1,2-a]pyrazine Syk inhibitors. This work culminated in the identification of GS-9973, 68, a highly selective and orally efficacious Syk inhibitor which is currently undergoing clinical evaluation for autoimmune and oncology indications. |
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| AbstractList | Spleen tyrosine kinase (Syk) is an attractive drug target in autoimmune, inflammatory, and oncology disease indications. The most advanced Syk inhibitor, R406, 1 (or its prodrug form fostamatinib, 2), has shown efficacy in multiple therapeutic indications, but its clinical progress has been hampered by dose-limiting adverse effects that have been attributed, at least in part, to the off-target activities of 1. It is expected that a more selective Syk inhibitor would provide a greater therapeutic window. Herein we report the discovery and optimization of a novel series of imidazo[1,2-a]pyrazine Syk inhibitors. This work culminated in the identification of GS-9973, 68, a highly selective and orally efficacious Syk inhibitor which is currently undergoing clinical evaluation for autoimmune and oncology indications. |
| Author | Gallion, Steve Maciejewski, Patricia Di Paolo, Julie A Lansdon, Eric B Kropf, Jeffrey E Blomgren, Peter Maclin, Deborah Mitchell, Scott A Macaluso, Jennifer Rossi, Ann Marie Barbosa, James Currie, Kevin S Whitney, J. Andrew Rong, Hong Lee, Tony Zhao, Zhongdong Xu, Jianjun |
| AuthorAffiliation | Department of Chemistry Department of Informatics & Modeling Department of Biology Atheon Pharma Inc Department of Structural Chemistry Gilead Sciences, Inc Department of Drug Metabolism |
| AuthorAffiliation_xml | – name: – name: Department of Drug Metabolism – name: Department of Chemistry – name: Department of Structural Chemistry – name: Department of Informatics & Modeling – name: Gilead Sciences, Inc – name: Department of Biology – name: Atheon Pharma Inc |
| Author_xml | – sequence: 1 givenname: Kevin S surname: Currie fullname: Currie, Kevin S – sequence: 2 givenname: Jeffrey E surname: Kropf fullname: Kropf, Jeffrey E – sequence: 3 givenname: Tony surname: Lee fullname: Lee, Tony – sequence: 4 givenname: Peter surname: Blomgren fullname: Blomgren, Peter – sequence: 5 givenname: Jianjun surname: Xu fullname: Xu, Jianjun – sequence: 6 givenname: Zhongdong surname: Zhao fullname: Zhao, Zhongdong – sequence: 7 givenname: Steve surname: Gallion fullname: Gallion, Steve – sequence: 8 givenname: J. Andrew surname: Whitney fullname: Whitney, J. Andrew – sequence: 9 givenname: Deborah surname: Maclin fullname: Maclin, Deborah – sequence: 10 givenname: Eric B surname: Lansdon fullname: Lansdon, Eric B – sequence: 11 givenname: Patricia surname: Maciejewski fullname: Maciejewski, Patricia – sequence: 12 givenname: Ann Marie surname: Rossi fullname: Rossi, Ann Marie – sequence: 13 givenname: Hong surname: Rong fullname: Rong, Hong – sequence: 14 givenname: Jennifer surname: Macaluso fullname: Macaluso, Jennifer – sequence: 15 givenname: James surname: Barbosa fullname: Barbosa, James – sequence: 16 givenname: Julie A surname: Di Paolo fullname: Di Paolo, Julie A – sequence: 17 givenname: Scott A surname: Mitchell fullname: Mitchell, Scott A email: scotta.mitchell@gilead.com |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/24779514$$D View this record in MEDLINE/PubMed |
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| Keywords | RHEUMATOID-ARTHRITIS POTENT ACTIVATION SYK MODELS INFLAMMATION FOSTAMATINIB DISODIUM DISEASE NON-HODGKIN-LYMPHOMA EXPRESSION |
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| Snippet | Spleen tyrosine kinase (Syk) is an attractive drug target in autoimmune, inflammatory, and oncology disease indications. The most advanced Syk inhibitor, R406,... |
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| SubjectTerms | Administration, Oral Animals Cells, Cultured Chemistry, Medicinal Drug Discovery Humans Indazoles - administration & dosage Indazoles - chemistry Indazoles - pharmacology Life Sciences & Biomedicine Magnetic Resonance Spectroscopy Mice Pharmacology & Pharmacy Protein Kinase Inhibitors - administration & dosage Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacology Protein-Tyrosine Kinases - antagonists & inhibitors Pyrazines - administration & dosage Pyrazines - chemistry Pyrazines - pharmacology Rats Science & Technology Spectrometry, Mass, Electrospray Ionization Spleen - drug effects Spleen - enzymology Structure-Activity Relationship |
| Title | Discovery of GS-9973, a Selective and Orally Efficacious Inhibitor of Spleen Tyrosine Kinase |
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