Design, synthesis and evaluation of novel hydroxyamides as orally available anticonvulsants.
Themisone, also known as Atrolactamide, was found, in the 1950s, to be a very potent anticonvulsant. It was hypothesized that the -CF(3) substitution would maintain the anticonvulsant activity. Anticonvulsant testing of our novel compounds by the National Institute of Health's Anticonvulsant Screening Project of the Antiepileptic Drug Discovery Program identified analogue 1, 3,3,3-trifluoro-2-hydroxy-2-phenyl-propionamide, to have potent anticonvulsant activity (MES ED(50) of 9.9 mg/kg, ScMET ED(50) of 34 mg/kg and TD(50) of 100 mg/kg). Therefore, a diverse range of analogues were synthesized utilizing multiple synthetic pathways to explore the structure-activity relationship. Patch clamp electrophysiology experiments demonstrate that compound 1 is an effective T-type calcium channel blocker. Altogether, these results suggest these compounds as a class of orally available anticonvulsants.
Department of Chemistry, University of Virginia, Charlottesville, VA 22904, USA.
Hilary A
HA
Schenck
Paul W
PW
Lenkowski
Indrani
I
Choudhury-Mukherjee
Seong-Hoon
SH
Ko
James P
JP
Stables
Manoj K
MK
Patel
Milton L
ML
Brown
D000284:Administration, Oral; D000577:Amides / Q000138:chemical synthesis / Q000493:pharmacokinetics; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D001682:Biological Availability; D002121:Calcium Channel Blockers / Q000138:chemical synthesis / Q000493:pharmacokinetics; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006880:Hydroxy Acids / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D009474:Neurons / Q000187:drug effects; D018408:Patch-Clamp Techniques; D051381:Rats; D012640:Seizures / Q000188:drug therapy / Q000517:prevention & control; D013329:Structure-Activity Relationship
D000577:Amides; D000927:Anticonvulsants; D002121:Calcium Channel Blockers; D006880:Hydroxy Acids