Benzofuranyl ureas with potent cardiovascular teratogenicity in rats.
Studies of embryo-fetal development in rats were conducted with two 5-lipoxygenase inhibitors. SB-202235 (1,000 mg/kg/day) or SB-210661 (50, 100, or 500 mg/kg/day) was administered orally by gavage to female rats on days 6-17 postcoitus (pc) or days 7-16 pc. SB-202235 (1,000 mg/kg/day) and SB-210661 (100 mg/kg/day) reduced maternal body weight gain for the treatment period by 16% and 21%, respectively, relative to controls. SB-202235 (1,000 mg/kg/day) or SB-210661 (50 or 100 mg/kg/day), did not affect numbers of resorptions, dead or live fetuses/litter, but 500 mg/kg/day of SB-210661 caused 100% embryo lethality. SB-202235 (1,000 mg/kg/day) and SB-210661 (50 and 100 mg/kg/day) reduced fetal body weight by 15-30% and produced extensive cardiovascular malformations, as well as diaphragmatic hernias. SB-210661 also caused thymic abnormalities and cryptorchidism. Cardiovascular defects included abnormalities in aorticopulmonary septation, the aortic arch, pulmonary trunk, and ventricular septal defects are discussed relative to comparable human syndromes of cardiovascular malformation.
Solomon
H M
HM
SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406-0939, USA.
Wier
P J
PJ
Johnson
C M
CM
Posobiec
L M
LM
Rendemonti
J E
JE
Rumberger
D F
DF
D000014:Abnormalities, Drug-Induced / Q000196:embryology; D000818:Animals; D001013:Aorta, Thoracic / Q000002:abnormalities / Q000187:drug effects / Q000196:embryology; D001572:Benzofurans / Q000633:toxicity*; D002319:Cardiovascular System / Q000187:drug effects* / Q000196:embryology / Q000473:pathology; D003456:Cryptorchidism / Q000139:chemically induced / Q000196:embryology; D010064:Embryo Implantation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000633:toxicity*; D004947:Esophagus / Q000098:blood supply; D005260:Female; D020567:Fetal Weight / Q000187:drug effects; D005333:Fetus / Q000002:abnormalities / Q000098:blood supply / Q000187:drug effects; D006548:Hernia, Diaphragmatic / Q000139:chemically induced / Q000196:embryology; D016859:Lipoxygenase Inhibitors; D008297:Male; D008431:Maternal-Fetal Exchange; D011247:Pregnancy; D011651:Pulmonary Artery / Q000002:abnormalities / Q000187:drug effects / Q000196:embryology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013047:Specific Pathogen-Free Organisms; D013348:Subclavian Artery / Q000002:abnormalities / Q000187:drug effects / Q000196:embryology; D013723:Teratogens / Q000633:toxicity*; D013950:Thymus Gland / Q000002:abnormalities / Q000187:drug effects / Q000196:embryology; D014508:Urea / Q000031:analogs & derivatives* / Q000633:toxicity; D014599:Uterus / Q000187:drug effects / Q000473:pathology
D001572:Benzofurans; D004791:Enzyme Inhibitors; D016859:Lipoxygenase Inhibitors; C094196:N-hydroxy-N-(2,3-dihydro-6-phenylmethoxy-3-benzofuranyl)urea; C111788:SB 210661; D013723:Teratogens; D014508:Urea