title: Synthetic studies on mitotic kinesin Eg5 inhibitors: synthesis and structure-activity relationships of novel 2,4,5-substituted-1,3,4-thiadiazoline derivatives.
abstract: The 2,4,5-substituted-1,3,4-thiadiazoline derivative 1a has been identified as a new class of mitotic kinesin Eg5 inhibitor. With the aim of enhancement of the mitotic phase accumulation activity, structure optimization of side chains at the 2-, 4-, and 5-positions of the 1,3,4-thiadiazoline ring of 1a was performed. The introduction of sulfonylamino group at the side chain at the 5-position and bulky acyl group at the 2- and 4-position contributed to a significant increase in the mitotic phase accumulation activity and Eg5 inhibitory activity. As a result, a series of optically active compounds exhibited an increased antitumor activity in a human ovarian cancer xenograft mouse model that was induced by oral administration.
authors.affiliation: Fuji Research Park, Research Division, Kyowa Hakko Kirin Co., Ltd, 1188 Shimotogari, Nagaizumi-cho, Suntou-gun, Shizuoka 411-8731, Japan. Electronic address: junichiro.yamamoto@kyowa-kirin.co.jp.
authors.forename: Junichiro
authors.initials: J
authors.lastname: Yamamoto
authors.affiliation: Fuji Research Park, Research Division, Kyowa Hakko Kirin Co., Ltd, 1188 Shimotogari, Nagaizumi-cho, Suntou-gun, Shizuoka 411-8731, Japan.
authors.forename: Nobuyoshi
authors.initials: N
authors.lastname: Amishiro
authors.affiliation: Fuji Research Park, Research Division, Kyowa Hakko Kirin Co., Ltd, 1188 Shimotogari, Nagaizumi-cho, Suntou-gun, Shizuoka 411-8731, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Kato
authors.affiliation: Fuji Research Park, Research Division, Kyowa Hakko Kirin Co., Ltd, 1188 Shimotogari, Nagaizumi-cho, Suntou-gun, Shizuoka 411-8731, Japan.
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Ohta
authors.affiliation: Fuji Research Park, Research Division, Kyowa Hakko Kirin Co., Ltd, 1188 Shimotogari, Nagaizumi-cho, Suntou-gun, Shizuoka 411-8731, Japan.
authors.forename: Yoji
authors.initials: Y
authors.lastname: Ino
authors.affiliation: Fuji Research Park, Research Division, Kyowa Hakko Kirin Co., Ltd, 1188 Shimotogari, Nagaizumi-cho, Suntou-gun, Shizuoka 411-8731, Japan.
authors.forename: Mitsuharu
authors.initials: M
authors.lastname: Araki
authors.affiliation: Fuji Research Park, Research Division, Kyowa Hakko Kirin Co., Ltd, 1188 Shimotogari, Nagaizumi-cho, Suntou-gun, Shizuoka 411-8731, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Tsujita
authors.affiliation: Fuji Research Park, Research Division, Kyowa Hakko Kirin Co., Ltd, 1188 Shimotogari, Nagaizumi-cho, Suntou-gun, Shizuoka 411-8731, Japan.
authors.forename: Seiho
authors.initials: S
authors.lastname: Okamoto
authors.affiliation: Fuji Research Park, Research Division, Kyowa Hakko Kirin Co., Ltd, 1188 Shimotogari, Nagaizumi-cho, Suntou-gun, Shizuoka 411-8731, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Fuji Research Park, Research Division, Kyowa Hakko Kirin Co., Ltd, 1188 Shimotogari, Nagaizumi-cho, Suntou-gun, Shizuoka 411-8731, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Kusaka
authors.affiliation: Fuji Research Park, Research Division, Kyowa Hakko Kirin Co., Ltd, 1188 Shimotogari, Nagaizumi-cho, Suntou-gun, Shizuoka 411-8731, Japan.
authors.forename: Shiro
authors.initials: S
authors.lastname: Akinaga
authors.affiliation: Fuji Research Park, Research Division, Kyowa Hakko Kirin Co., Ltd, 1188 Shimotogari, Nagaizumi-cho, Suntou-gun, Shizuoka 411-8731, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Yamashita
authors.affiliation: Fuji Research Park, Research Division, Kyowa Hakko Kirin Co., Ltd, 1188 Shimotogari, Nagaizumi-cho, Suntou-gun, Shizuoka 411-8731, Japan.
authors.forename: Ryuichiro
authors.initials: R
authors.lastname: Nakai
authors.affiliation: Fuji Research Park, Research Division, Kyowa Hakko Kirin Co., Ltd, 1188 Shimotogari, Nagaizumi-cho, Suntou-gun, Shizuoka 411-8731, Japan.
authors.forename: Chikara
authors.initials: C
authors.lastname: Murakata
mesh_terms: D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D053778:Thiazolidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; C470243:KIF11 protein, human; D053778:Thiazolidines; D016547:Kinesins
keywords: Mitotic kinesin Eg5 inhibitor; Thiadiazoline derivatives