Design and Synthesis of the First Generation of Novel Potent, Selective, and in Vivo Active (Benzothiazol-2-yl)acetonitrile Inhibitors of the c-Jun N-Terminal Kinase
| Autor: | Steve Arkinstall, Pascale Gaillard, Denise Gretener, Cedric Szyndralewiez, Dennis Church, Christian Chabert, Vittoria Ardissone, Rocco Cirillo, Jean-Pierre Gotteland, Isabelle Jeanclaude-Etter, Montserrat Camps, Serge Halazy, Yves Cambet, Anthony Nichols, Pierre-Alain Vitte |
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| Rok vydání: | 2005 |
| Předmět: |
Male
Acetonitriles Pyrimidine Stereochemistry Arthritis Chemical synthesis Jurkat Cells Mice Structure-Activity Relationship chemistry.chemical_compound In vivo Drug Discovery medicine Animals Humans Structure–activity relationship Benzothiazoles Protein kinase A Mice Inbred C3H biology Tumor Necrosis Factor-alpha Kinase Chemistry Anti-Inflammatory Agents Non-Steroidal JNK Mitogen-Activated Protein Kinases medicine.disease Arthritis Experimental Rats Thiazoles Mice Inbred DBA Antirheumatic Agents Mitogen-activated protein kinase biology.protein Molecular Medicine |
| Zdroj: | Journal of Medicinal Chemistry. 48:4596-4607 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | Several lines of evidence support the hypothesis that c-Jun N-terminal kinase (JNKs) plays a critical role in a wide range of diseases including cell death (apoptosis)-related disorders (neurodegenerative diseases, brain, heart, and renal ischemia, epilepsy) and inflammatory disorders (multiple sclerosis, rheumatoid arthritis, inflammatory bowel diseases). Screening of our internal compound collection for inhibitors of JNK3 led to the identification of (benzothiazol-2-yl)acetonitrile derivatives as potent and selective JNK1, -2, -3 inhibitors. Starting from initial hit 1 (AS007149), the chemistry and initial structure-activity relationship (SAR) of this novel and unique kinase inhibitor template were explored. Investigation of the SAR rapidly revealed that the benzothiazol-2-ylacetonitrile pyrimidine core was crucial to retain a good level of potency on rat JNK3. Therefore, compound 6 was further optimized by exploring a number of distal combinations in place of the chlorine atom. This led to the observation that the presence of an aromatic group, two carbons away from the aminopyrimidine moiety and bearing substituents conferring hydrogen bond acceptor (HBA) properties, could improve the potency. Further improvements to the biological and biopharmaceutical profile of the most promising compounds were performed, resulting in the discovery of compound 59 (AS601245). The in vitro and in vivo anti-inflammatory potential of this new JNK inhibitor was investigated and found to demonstrate efficacy per oral route in an experimental model of rheumatoid arthritis (RA). |
| Databáze: | OpenAIRE |
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