Benzofuranyl ureas with potent cardiovascular teratogenicity in rats

Studies of embryo-fetal development in rats were conducted with two 5-lipox ygenase inhibitors. SB-202235 (1,000 mg/kg/day) or SB-210661 (50, 100, or 5 00 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-210651 (50 or 100 mg/kg/day), did not affect numbers of resorpt ions, dead or live fetuses/litter, but 500 mg/kg/day of SB-210661, caused 1 00% 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% acid produced extensive car diovascular malformations, as well as diaphragmatic hernias. SB-210661 also caused thymic abnormalities and cryptorchidism, Cardiovascular defects inc luded abnormalities in aorticopulmonary septation, the aortic arch, pulmona ry trunk, and ventricular septal defects ave discussed relative to comparab le human syndromes of cardiovascular malformation. (C) 2000 Wiley-Liss, Inc .