Maximizing diversity from a kinase screen: identification of novel and selective pan-Trk inhibitors for chronic pain.

Abstract

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.

• Authors: Shawn J Stachel, John M Sanders, Darrell A Henze, Mike T Rudd, Hua-Poo Su, Yiwei Li, Kausik K Nanda, Melissa S Egbertson, Peter J Manley, Kristen L G Jones, Edward J Brnardic, Ahren Green, Jay A Grobler, Barbara Hanney, Michael Leitl, Ming-Tain Lai, Vandna Munshi, Dennis Murphy, Keith Rickert, Daniel Riley, Alicja Krasowska-Zoladek, Christopher Daley, Paul Zuck, Stephanie A Kane, Mark T Bilodeau
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 57 Issue 13 Pg. 5800-16 (Jul 10 2014) ISSN: 1520-4804 [Electronic] United States
• PMID: 24914455 (Publication Type: Journal Article)

Chemical References

• Indoles
• Ligands
• Protein Kinase Inhibitors
• Pyrimidines
• Small Molecule Libraries
• Triazoles
• Urea
• Receptor, trkA

Topics

• Animals
• Chronic Pain (drug therapy)
• Drug Evaluation, Preclinical
• Humans
• Indoles (chemistry, pharmacokinetics)
• Ligands
• Models, Molecular
• Protein Kinase Inhibitors (chemistry, pharmacokinetics)
• Pyrimidines (chemistry, pharmacokinetics)
• Rats
• Receptor, trkA (antagonists & inhibitors)
• Small Molecule Libraries (therapeutic use)
• Structure-Activity Relationship
• Triazoles (chemistry, pharmacokinetics)
• Urea (analogs & derivatives, chemistry, pharmacokinetics)