title: Synthesis, structure-activity relationships, and anticonvulsant activities of 2-amino-4H-pyrido[3,2-e][1,3]thiazin-4-one derivatives as orally active AMPA receptor antagonists.
abstract: As part of a program aimed at discovering orally active 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor antagonists, we screened our compound library and identified 2-[allyl(4-methylphenyl)amino]-4H-pyrido[3,2-e][1,3]thiazin-4-one (7) as a lead compound that inhibited kainate-induced neurotoxicity mediated by AMPA receptors in rat hippocampal cultures. Structure-activity relationship studies of a series of 2-amino-4H-pyrido[3,2-e][1,3]thiazin-4-one derivatives revealed that substituents on the phenyl ring attached to the 2-amino group and the 4H-pyrido[3,2-e][1,3]thiazin-4-one ring system play an important role in inhibitory activity against kainate-induced neurotoxicity. Several analogs bearing a phenyl group with a 4-substituent or five- or six-membered ring fused at the 3,4-positions exhibited potent inhibitory activity against kainate-induced neurotoxicity. Further, some of these compounds exhibited significant suppression of maximal electroshock seizure in mice following oral administration. Of these compounds, 2-[(4-chlorophenyl)(methyl)amino]-4H-pyrido[3,2-e][1,3]thiazin-4-one (16i) (YM928) demonstrated the most potent inhibitory effect with an ED50 value of 7.4mg/kg.
authors: Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan. Electronic address: hiroshi.inami@astellas.com.
authors: Hiroshi
authors: H
authors: Inami
authors: Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
authors: Jun-ichi
authors: J
authors: Shishikura
authors: Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
authors: Tomoyuki
authors: T
authors: Yasunaga
authors: Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
authors: Kazushige
authors: K
authors: Ohno
authors: Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
authors: Hiroshi
authors: H
authors: Yamashita
authors: Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
authors: Kota
authors: K
authors: Kato
authors: Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
authors: Shuichi
authors: S
authors: Sakamoto
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000969:Antinematodal Agents / Q000633:toxicity; D002478:Cells, Cultured; D004597:Electroshock / Q000009:adverse effects; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D007608:Kainic Acid / Q000633:toxicity; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012640:Seizures / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D013329:Structure-Activity Relationship; D013843:Thiazines / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: C475769:2-(N-(4-chlorophenyl)-N-methylamino)-4H-pyrido(3,2-e)-1,3-thiazin-4-one; D000927:Anticonvulsants; D000969:Antinematodal Agents; D011725:Pyridines; D018091:Receptors, AMPA; D013843:Thiazines; D007608:Kainic Acid
keywords: AMPA receptor antagonist; Anticonvulsant; Kainate; Neurotoxicity; Noncompetitive