SAR studies around a series of triazolopyridines as potent and selective PI3Kγ inhibitors
| Autor: | Warren Miller, Giovanna Bergamini, Mihiro Sunose, Jess Taylor, Gitte Neubauer, Andrew Cansfield, Nigel Ramsden, Katie Ellard, Kathryn Bell |
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| Rok vydání: | 2012 |
| Předmět: |
Stereochemistry
Pyridines Clinical Biochemistry Pharmaceutical Science Administration Oral Biochemistry Mice Structure-Activity Relationship Cell Line Tumor Microsomes Drug Discovery Animals Class Ib Phosphatidylinositol 3-Kinase Humans Protein Isoforms Kinome Computer Simulation Molecular Biology Phosphoinositide-3 Kinase Inhibitors Binding Sites Chemistry Arthritis Organic Chemistry Key features Protein Structure Tertiary Rats Disease Models Animal Molecular Medicine Triazolopyridine A kinase Selectivity Collagen-induced arthritis Half-Life |
| Zdroj: | Bioorganicmedicinal chemistry letters. 22(16) |
| ISSN: | 1464-3405 |
| Popis: | Herein we describe the SAR of a novel series of 6-aryl-2-amino-triazolopyridines as potent and selective PI3Kγ inhibitors. The 6-aryl-triazolopyridine core was identified by chemoproteomic screening of a kinase focused library. Rapid chemical expansion around a bi-functional core identified the key features required for PI3Kγ activity and selectivity. The series was optimized to afford 43 (CZC19945), a potent PI3Kγ inhibitor with high oral bioavailability and selectivity over PI3Kα and PI3Kδ. Modification to the core afforded 53 (CZC24832) which showed increased selectivity over the entire kinome in particular over PI3Kβ. |
| Databáze: | OpenAIRE |
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