title: Tetramethylcyclopropyl analogue of the leading antiepileptic drug, valproic acid: evaluation of the teratogenic effects of its amide derivatives in NMRI mice.
abstract: BACKGROUND
  Although valproic acid (VPA) is used extensively for treating various kinds of epilepsy, it causes hepatotoxicity and teratogenicity. In an attempt to develop a more potent and safer second generation to VPA drug, the amide derivatives of the tetramethylcyclopropyl VPA analogue, 2,2,3,3-tetramethylcyclopropanecarboxamide (TMCD), N-methyl-TMCD (MTMCD), 4-(2,2,3,3-tetramethylcyclopropanecarboxamide)-benzenesulfonamide (TMCD-benzenesulfonamide), and 5-(TMCD)-1,3,4-thiadiazole-2-sulfonamide (TMCD-thiadiazolesulfonamide) were synthesized and shown to have more potent anticonvulsant activity than VPA. Teratogenic effects of these CNS-active compounds were evaluated in Naval Medical Research Institute (NMRI) mice susceptible to VPA-induced teratogenicity by comparing them to those of VPA.
  
  
  METHODS
  Pregnant NMRI mice were given a single sc injection of either VPA or TMC-amide derivatives on gestation day 8.5, and then the live fetuses were examined to detect any external malformations on gestation day 18. After double-staining for bone and cartilage, their skeletons were examined.
  
  
  RESULTS
  In contrast to VPA, which induced NTDs in a high number of fetuses at 2.4-4.8 mmol/kg, TMCD, TMCD-benzenesulfonamide, and TMCD-thiadiazolesulfonamide at 4.8 mmol/kg and MTMCD at 3.6 mmol/kg did not induce a significant number of NTDs. TMCD-thiadiazolesulfonamide exhibited a potential to induce limb defects in fetuses. Skeletal examination also revealed that fetuses exposed to all four of the tetramethylcyclopropanecarboxamide derivatives developed vertebral and rib abnormalities less frequently than those exposed to VPA. Our results established that TMCD, MTMCD, and TMCD-benzenesulfonamide are distinctly less teratogenic than VPA in NMRI mice.
  
  
  CONCLUSIONS
  The CNS-active amides containing a tetramethylcyclopropanecarbonyl moiety demonstrated better anticonvulsant potency compared to VPA and a lack of teratogenicity, which makes these compounds good second-generation VPA antiepileptic drug candidates.
authors.affiliation: Drug Safety Research Laboratories, Astellas Pharma Inc., Osaka, Japan.
authors.forename: Akinobu
authors.initials: A
authors.lastname: Okada
authors.forename: Yuko
authors.initials: Y
authors.lastname: Onishi
authors.forename: Boris
authors.initials: B
authors.lastname: Yagen
authors.forename: Jakob Avi
authors.initials: JA
authors.lastname: Shimshoni
authors.forename: Dan
authors.initials: D
authors.lastname: Kaufmann
authors.forename: Meir
authors.initials: M
authors.lastname: Bialer
authors.forename: Michio
authors.initials: M
authors.lastname: Fujiwara
mesh_terms: D000014:Abnormalities, Drug-Induced; D000577:Amides / Q000009:adverse effects / Q000737:chemistry; D000818:Animals; D000927:Anticonvulsants / Q000009:adverse effects* / Q000737:chemistry; D003521:Cyclopropanes / Q000009:adverse effects / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004827:Epilepsy / Q000188:drug therapy*; D005260:Female; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D011247:Pregnancy; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000009:adverse effects / Q000737:chemistry; D013830:Thiadiazoles / Q000009:adverse effects / Q000737:chemistry; D014635:Valproic Acid / Q000009:adverse effects / Q000031:analogs & derivatives*; D000096926:Benzenesulfonamides
chemical_list: D000577:Amides; D000927:Anticonvulsants; D003521:Cyclopropanes; D013449:Sulfonamides; D013830:Thiadiazoles; D014635:Valproic Acid; D000096926:Benzenesulfonamides; C116673:2,2,3,3-tetramethylcyclopropane carboxamide