- Maximizing diversity from a kinase screen: Identification of novel and selective pan-Trk inhibitors for chronic pain
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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.
- Stachel, Shawn J.,Sanders, John M.,Henze, Darrell A.,Rudd, Mike T.,Su, Hua-Poo,Li, Yiwei,Nanda, Kausik K.,Egbertson, Melissa S.,Manley, Peter J.,Jones, Kristen L. G.,Brnardic, Edward J.,Green, Ahren,Grobler, Jay A.,Hanney, Barbara,Leitl, Michael,Lai, Ming-Tain,Munshi, Vandna,Murphy, Dennis,Rickert, Keith,Riley, Daniel,Krasowska-Zoladek, Alicja,Daley, Christopher,Zuck, Paul,Kane, Stephanie A.,Bilodeau, Mark T.
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p. 5800 - 5816
(2014/08/05)
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- The synthesis and SAR study of phenylalanine-derived (Z)-5-arylmethylidene rhodanines as anti-methicillin-resistant Staphylococcus aureus (MRSA) compounds
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A focused library of rhodanine compounds containing novel substituents at the C5-position was synthesized and tested in vitro against a panel of clinically relevant MRSA strains. The present SAR study was based on our lead compound 1 (MIC = 1.95 μg/mL), with a focus on identifying optimal C5-arylidene substituents. In order to obtain this objective, we condensed several unique aromatic aldehydes with phenylalanine-derived rhodanine intermediates to obtain C5-substituted target rhodanine compounds for evaluation as anti-MRSA compounds. These efforts produced three compounds with significant efficacy: 23, 32 and 44, with MIC values ranging from 0.98 to 1.95 μg/mL against all tested MRSA strains as compared to the reference antibiotics penicillin G (MIC = 15.60-250.0 μg/mL) and ciprofloxacin (MIC = 7.80-62.50 μg/mL) and comparable to that of vancomycin (MIC = 0.48 μg/mL). In addition, compounds 24, 28, 37, 41, 46 and 48 (MIC = 1.95-3.90 μg/mL) were efficacious against all MRSA strains. The majority of the synthesized compounds had bactericidal activity at concentrations only two to fourfold higher than their MIC. Overall, the results suggest that compounds 23, 32 and 44 may be of potential use in the treatment of MRSA infections.
- Patel, Bhargav A.,Ashby Jr., Charles R.,Hardej, Diane,Talele, Tanaji T.
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supporting information
p. 5523 - 5527
(2013/10/01)
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