3-amino-benzo[d]isoxazoles as novel multitargeted inhibitors of receptor tyrosine kinases.
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 ED 50 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.
Ji
Zhiqin
Z
Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064-6100, USA. zhiqin.ji@abbott.com.
Ahmed
Asma A
AA
Albert
Daniel H
DH
Bouska
Jennifer J
JJ
Bousquet
Peter F
PF
Cunha
George A
GA
Diaz
Gilbert
G
Glaser
Keith B
KB
Guo
Jun
J
Harris
Christopher M
CM
Li
Junling
J
Marcotte
Patrick A
PA
Moskey
Maria D
MD
Oie
Tetsuro
T
Pease
Lori
L
Soni
Nirupama B
NB
Stewart
Kent D
KD
Davidsen
Steven K
SK
Michaelides
Michael R
MR
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D001665:Binding Sites; D001682:Biological Availability; D002199:Capillary Permeability / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D004487:Edema / Q000188:drug therapy; D005260:Female; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D041681:NIH 3T3 Cells; D010080:Oxazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D010766:Phosphorylation; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014599:Uterus / Q000098:blood supply; D023041:Xenograft Model Antitumor Assays
C529287:1-(4-(3-amino-7-methoxybenzo(d)isoxazol-4-yl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D007555:Isoxazoles; D010080:Oxazoles; D010671:Phenylurea Compounds; D017479:Receptors, Platelet-Derived Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor