Bioorganic and Medicinal Chemistry p. 4133 - 4141 (2003)
Update date:2022-08-05
Topics:
Grimm, Jonathan B.
Stables, James P.
Brown, Milton L.
Epilepsy afflicts 1-2% of the world's population and often goes untreated; nearly 70% of those with a form of epilepsy fail to receive proper treatment. Therefore, there is great demand for the design of novel, effective anticonvulsants to combat epilepsy in its numerous forms. Previously, α-hydroxy-α-phenylcaprolactam was found to have rather potent antiepileptic activity [anti-maximal electroshock (MES) ED50=63 mg/ kg and anti-subcutaneous Metrazol (scMet) ED50=74 mg/kg] when administered intraperitoneally in mice. We focused our attention on the development of this compound through traditional medicinal chemistry techniques - including the Topliss approach, isosteric replacement, methylene insertion, and rigid analogue approach - in the hopes of determining the effect of caprolactam α-substitution and other structural modifications on anticonvulsant activity. A number of the desired targets were successfully synthesized and submitted to the Anticonvulsant Screening Program of the National Institute of Neurological Disorders and Stroke (NINDS). Phase I results were quite promising for at least three of the compounds: α-ethynyl-α-hydroxycaprolactam (10), α-benzyl-α-hydroxycaprolactam (11), and α-hydroxy-α-(phenylethynyl)caprolactam (13). Phase II results for 11 strongly suggested it as a new structural class for further development, as it exhibited an anti-MES T.I. in excess of 4.0. Further, the potent activity of 13 in all models also pointed to the substituted alkynylcaprolactams as a new anticonvulsant structural class.
View MoreContact:0086-573-82201031
Address:Jiaxing Industrial Park, Daqiao Town, Jiaxing
Contact:+86-21-54391580
Address:Room 502,No.65,Lane 2388 Hongxin Road,Shanghai,China
Shanghai Hanhong Scientific Co.,Ltd.
website:http://www.chemvia.com
Contact:+86-21-64541543,54280654,13918533501
Address:Jiachuan Road 245
Chongqing Changfeng Chemical Co., Ltd.
website:http://www.changfengchem.com
Contact:+86-23-67896333
Address:30th Floor, Longhu Ziduxingzuo Building A, 1st Branch,YuSong Rd., Yubei District, Chongqing, China
Contact:+86-519-86623222
Address:29F/D, 99 Yanling West Road, Changzhou, Jiangsu, China
Doi:10.1016/j.tetlet.2003.09.169
(2003)Doi:10.1021/ja01555a054
(1958)Doi:10.1002/jhet.5570330122
(1996)Doi:10.1016/j.poly.2003.07.007
(2003)Doi:10.1021/ja060369+
(2006)Doi:10.1021/ol0358399
(2003)