Design and synthesis of dihydroindazolo[5,4- a]pyrrolo[3,4- c]carbazole oximes as potent dual inhibitors of TIE-2 and VEGF-R2 receptor tyrosine kinases

Fused dihydroindazolopyrrolocarbazole oximes have been identified as low nanomolar, potent dual TIE-2 and VEGF-R2 receptor tyrosine kinase inhibitors with excellent cellular potency. Development of the structure–activity relationships (SAR) led to identification of compounds 35 and 40 as potent, sel...

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Veröffentlicht in:	Bioorganic & medicinal chemistry 2008-03, Vol.18 (6), p.1916-1921
Hauptverfasser:	Dandu, Reddeppareddy, Zulli, Allison L., Bacon, Edward R., Underiner, Ted, Robinson, Candy, Chang, Hong, Miknyoczki, Sheila, Grobelny, Jennifer, Ruggeri, Bruce A., Yang, Shi, Albom, Mark S., Angeles, Thelma S., Aimone, Lisa D., Hudkins, Robert L.
Format:	Artikel
Sprache:	eng
Schlagworte:	Administration, Oral Angiogenesis Angiogenesis Inhibitors - chemical synthesis Angiogenesis Inhibitors - pharmacokinetics Angiogenesis Inhibitors - pharmacology Animals Antineoplastic agents Biological and medical sciences Cell Proliferation - drug effects Cells, Cultured Drug Design Endothelium, Vascular - cytology Endothelium, Vascular - drug effects Endothelium, Vascular - metabolism General aspects Hemangiosarcoma - blood supply Hemangiosarcoma - drug therapy Hemangiosarcoma - enzymology Humans Medical sciences Melanoma, Experimental - blood Melanoma, Experimental - blood supply Melanoma, Experimental - drug therapy Melanoma, Experimental - enzymology Molecular Structure Neovascularization, Pathologic Oximes - chemical synthesis Oximes - pharmacokinetics Oximes - pharmacology Pharmacology. Drug treatments Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - pharmacokinetics Protein Kinase Inhibitors - pharmacology Rats Receptor, TIE-2 - antagonists & inhibitors Receptor, TIE-2 - metabolism Structure-Activity Relationship TIE-2 Tyrosine kinase inhibitors Umbilical Veins Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors Vascular Endothelial Growth Factor Receptor-2 - metabolism VEGF-R2
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Zusammenfassung:	Fused dihydroindazolopyrrolocarbazole oximes have been identified as low nanomolar, potent dual TIE-2 and VEGF-R2 receptor tyrosine kinase inhibitors with excellent cellular potency. Development of the structure–activity relationships (SAR) led to identification of compounds 35 and 40 as potent, selective dual TIE-2/VEGF-R2 inhibitors with favorable pharmacokinetic properties. Compound 35 was orally active in tumor models with no observed toxicity.
ISSN:	0960-894X 0968-0896 1464-3405 1464-3391
DOI:	10.1016/j.bmcl.2008.02.001