3-Amino-benzo[d]isoxazoles as Novel Multitargeted Inhibitors of Receptor Tyrosine Kinases

• Published in: Journal of medicinal chemistry 2008-03, Vol.51 (5), p.1231-1241
• Main Authors: Ji, Zhiqin, Ahmed, Asma A, Albert, Daniel H, Bouska, Jennifer J, Bousquet, Peter F, Cunha, George, A, Diaz, Gilbert, Glaser, Keith B, Guo, Jun, Harris, Christopher M, Li, Junling, Marcotte, Patrick A, Moskey, Maria D, Oie, Tetsuro, Pease, Lori, Soni, Nirupama B, Stewart, Kent D, Davidsen, Steven K, Michaelides, Michael R
• Format: Article
• Language: English
• Subjects: Animals; Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis; Anti-Inflammatory Agents, Non-Steroidal - pharmacokinetics; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Binding Sites; Biological and medical sciences; Biological Availability; Capillary Permeability - drug effects; Cell Line; Cell Line, Tumor; Edema - drug therapy; Female; General aspects; Humans; Isoxazoles - chemical synthesis; Isoxazoles - pharmacokinetics; Isoxazoles - pharmacology; Medical sciences; Mice; Mice, Inbred BALB C; Models, Molecular; NIH 3T3 Cells; Oxazoles - chemical synthesis; Oxazoles - pharmacokinetics; Oxazoles - pharmacology; Pharmacology. Drug treatments; Phenylurea Compounds - chemical synthesis; Phenylurea Compounds - pharmacokinetics; Phenylurea Compounds - pharmacology; Phosphorylation; Receptors, Platelet-Derived Growth Factor - antagonists & inhibitors; Receptors, Vascular Endothelial Growth Factor - antagonists & inhibitors; Structure-Activity Relationship; Uterus - blood supply; Xenograft Model Antitumor Assays
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm701096v

A series of benzoisoxazoles and benzoisothiazoles have been synthesized and evaluated as inhibitors of receptor tyrosine kinases (RTKs). Structure–activity relationship studies led to the identification of 3-amino benzo[d]isoxazoles, incorporating a N,N′-diphenyl urea moiety at the 4-position that potently inhibited both the vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor families of RTKs. Within this series, orally bioavailable compounds possessing promising pharmacokinetic profiles were identified, and a number of compounds demonstrated in vivo efficacy in models of VEGF-stimulated vascular permeability and tumor growth. In particular, compound 50 exhibited an ED50 of 2.0 mg/kg in the VEGF-stimulated uterine edema model and 81% inhibition in the human fibrosarcoma (HT1080) tumor growth model when given orally at a dose of 10 mg/kg/day.