Different embryo-fetal toxicity effects for three VLA-4 antagonists.
BACKGROUND
VLA-4 (Very late antigen 4, integrin alpha4beta1) plays an important role in cell-cell interactions that are critical for development. Homozygous null knockouts of the alpha4 subunit of VLA-4 or VCAM-1 (cell surface ligand to VLA-4) in mice result in abnormal placental and cardiac development and embryo lethality. Objectives of the current study were to assess and compare the teratogenic potential of three VLA-4 antagonists.


METHODS
IVL745, HMR1031, and IVL984 were each evaluated by the subcutaneous route in standard embryo-fetal developmental toxicity studies in rats and rabbits. IVL984 was also evaluated in mice. Fetuses were examined externally, viscerally, and skeletally.


RESULTS
IVL745 did not cause significant maternal or fetal effects at doses up to 100 or 250 mg/kg/day in rats or rabbits, respectively. HMR1031 treatment resulted in marked maternal toxicity and slight fetal toxicity at the highest tested doses of 200 and 75 mg/kg/day in rats and rabbits, respectively. HMR1031 embryo-fetal effects consisted of slightly lower body weight and crown-rump length in rats and minor sternebral defects in rabbits. IVL984 treatment resulted in minimal maternal effects at doses up to 40, 15, and 100 mg/kg/day in rats, rabbits, and mice, respectively (excluding abortions in rabbits). However, marked developmental effects were observed at the lowest tested IVL984 doses, 1, 0.2, and 3 mg/kg/day in rats, rabbits, and mice, respectively. IVL984 embryo-fetal effects consisted of increased total post-implantation loss due to early resorptions and high incidences of cardiac malformations and skeletal malformations and/or variations. Notably, spiral septal defects were observed in up to 76% of rat fetuses and up to 58% of rabbit fetuses.


CONCLUSIONS
Dramatic differences in teratogenic potential were observed: IVL745 was not teratogenic, HMR1031 caused slight embryo-fetal effects at maternally-toxic doses, and IVL984 was a potent teratogen at doses where direct maternal toxicity was limited to abortions in rabbits. Prominent effects of IVL984 included embryo lethality and cardiac malformations including spiral septal defects in three species.
Crofts
F
F
Department of Drug Safety Evaluation, Aventis Inc., Bridgewater, New Jersey 08807, USA. Frances.Crofts@aventis.com
Pino
M
M
DeLise
B
B
Guittin
P
P
Barbellion
S
S
Brunel
P
P
Potdevin
S
S
Bergmann
B
B
Hofmann
T
T
Lerman
S
S
Clark
R L
RL
D000014:Abnormalities, Drug-Induced; D000818:Animals; D001555:Benzene Derivatives; D002450:Cell Communication; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions; D004622:Embryo, Mammalian / Q000187:drug effects*; D047108:Embryonic Development / Q000187:drug effects; D005260:Female; D006720:Homozygote; D007093:Imidazoles / Q000633:toxicity*; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors*; D018811:Maternal Exposure; D008431:Maternal-Fetal Exchange; D051379:Mice; D008956:Models, Chemical; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000633:toxicity*; D010671:Phenylurea Compounds / Q000633:toxicity*; D011247:Pregnancy; D011270:Pregnancy, Animal; D011422:Propionates / Q000633:toxicity*; D011817:Rabbits; D051381:Rats; D013045:Species Specificity; D013723:Teratogens / Q000494:pharmacology
C483465:(3S)-3-(((2S)-2-(4,4-dimethyl-3-(4-((((2-methylphenyl)amino)carbonyl)amino)benzyl)-2,5-dioxoimidazolidin-1-yl)-4-methylpentanoyl)amino)-3-phenylpropanoic acid; C487626:3-(N-(3,4-dimethoxybenzyl)-2-(2-(3-methoxy-4-(3-o-tolylureido)phenyl)acetylamino)acetamido)propanoic acid; D001555:Benzene Derivatives; C493781:IVL 984; D007093:Imidazoles; D039041:Integrin alpha4beta1; D010671:Phenylurea Compounds; D011422:Propionates; D013723:Teratogens; D010649:Phenylalanine