title: Discovery of benzothiazine derivatives as novel, orally-active anti-epileptic drug candidates with broad anticonvulsant effect.
abstract: In order to develop novel anti-epileptic drugs that are effective for both general and partial seizure, we conducted in vivo screening of our chemical library in the mice MES and sc-PTZ models and found the benzothiazine 1 as lead compound. Optimization of this compound led to the discovery of compound 7b, which showed potent anticonvulsant effect in the MES, scPTZ and rat amygdala kindling models. Since the chemical structure of 7b is different from that of any existing AED, it is suggested that 7b may have unique mechanism of action for relieving both partial and generalized epilepsy.
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd, 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan. Electronic address: tomoyuki-1-tanaka@ds-pharma.co.jp.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd, 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Nana
authors.initials: N
authors.lastname: Yajima
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd, 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Tanitame
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd, 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kiyoshi
authors.affiliation: Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd, 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Miura
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004597:Electroshock; D004827:Epilepsy / Q000188:drug therapy*; D007279:Injections, Subcutaneous; D007696:Kindling, Neurologic; D051379:Mice; D015394:Molecular Structure; D010433:Pentylenetetrazole / Q000008:administration & dosage; D051381:Rats; D012640:Seizures / Q000188:drug therapy*; D013329:Structure-Activity Relationship; D013843:Thiazines / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*
chemical_list: D000927:Anticonvulsants; D013843:Thiazines; D010433:Pentylenetetrazole
keywords: Amygdala kindling; Benzothiazine; Epilepsy; In vivo screening; MES; PTZ