Abstract
The hepatocyte growth factor (HGF)-c-Met signaling axis is involved in the mediation of many biological activities, including angiogenesis, proliferation, cell survival, cell motility, and morphogenesis. Dysregulation of c-Met signaling (e.g., overexpression or increased activation) is associated with the proliferation and metastasis of a wide range of tumor types, including breast, liver, lung, colorectal, gastric, bladder, and prostate, among others. Inhibiting the HGF-c-Met pathway is predicted to lead to anti-tumor effects in many cancers. Elaboration of the SAR around a series of 2,4-diaminopyrimidines led to a number of c-Met inhibitors in which pharmaceutical properties were modulated by substituents appended on the C2-benzazepinone ring. In particular, certain-3-amidobenzazepin-2-one analogs had improved oral bioavailability and were evaluated in PK/PD and efficacy models. Lead compounds demonstrated tumor stasis with partial regressions when evaluated in a GTL-16 tumor xenograft mouse model.
Copyright © 2011 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacokinetics
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Benzazepines / chemical synthesis
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Benzazepines / chemistry*
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Benzazepines / pharmacokinetics*
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Biological Availability
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Female
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Hepatocyte Growth Factor / antagonists & inhibitors
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Hepatocyte Growth Factor / metabolism
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Inhibitory Concentration 50
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Magnetic Resonance Spectroscopy
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Male
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Mice
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Mice, Nude
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Molecular Structure
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Neoplasms, Experimental / drug therapy
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Neoplasms, Experimental / enzymology
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Neoplasms, Experimental / metabolism*
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacokinetics
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Proto-Oncogene Proteins c-met / antagonists & inhibitors*
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Proto-Oncogene Proteins c-met / metabolism
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Pyrimidines / chemical synthesis
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Pyrimidines / chemistry*
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Pyrimidines / pharmacokinetics*
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Random Allocation
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Rats
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Rats, Sprague-Dawley
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Spectrometry, Mass, Electrospray Ionization
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Structure-Activity Relationship
Substances
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Antineoplastic Agents
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Benzazepines
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Protein Kinase Inhibitors
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Pyrimidines
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2,4-diaminopyrimidine
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Hepatocyte Growth Factor
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Proto-Oncogene Proteins c-met