Maximizing diversity from a kinase screen: identification of novel and selective pan-Trk inhibitors for chronic pain
| Autor: | Keith W. Rickert, Ming-Tain Lai, Daniel Riley, Melissa S. Egbertson, Mike T. Rudd, Kausik K. Nanda, Barbara Hanney, Shawn J. Stachel, Stephanie A. Kane, Jay A. Grobler, Ahren Iver Green, John M. Sanders, Christopher Daley, Paul Zuck, Vandna Munshi, Edward J. Brnardic, Kristen G. Jones, Darrell A. Henze, Alicja Krasowska-Zoladek, Hua-Poo Su, Mark T. Bilodeau, Yiwei Li, Dennis Murphy, Michael D. Leitl, Peter J. Manley |
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| Rok vydání: | 2014 |
| Předmět: |
Models
Molecular Indoles Drug Evaluation Preclinical Tropomyosin receptor kinase A Ligands Small Molecule Libraries Structure-Activity Relationship Drug Discovery Structure–activity relationship Potency Animals Humans Urea Receptor trkA Receptor Protein Kinase Inhibitors Ligand efficiency Kinase Chemistry Triazoles Small molecule Rats Pyrimidines nervous system Biochemistry Trk receptor Molecular Medicine Chronic Pain |
| Zdroj: | Journal of medicinal chemistry. 57(13) |
| ISSN: | 1520-4804 |
| Popis: | We have identified several series of small molecule inhibitors of TrkA with unique binding modes. The starting leads were chosen to maximize the structural and binding mode diversity derived from a high throughput screen of our internal compound collection. These leads were optimized for potency and selectivity employing a structure based drug design approach adhering to the principles of ligand efficiency to maximize binding affinity without overly relying on lipophilic interactions. This endeavor resulted in the identification of several small molecule pan-Trk inhibitor series that exhibit high selectivity for TrkA/B/C versus a diverse panel of kinases. We have also demonstrated efficacy in both inflammatory and neuropathic pain models upon oral dosing. Herein we describe the identification process, hit-to-lead progression, and binding profiles of these selective pan-Trk kinase inhibitors. |
| Databáze: | OpenAIRE |
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