title: Optimization of diaryl amine derivatives as kinesin spindle protein inhibitors.
abstract: Structure-activity relationship studies of diaryl amine-type KSP inhibitors were carried out. Diaryl amine derivatives with a pyridine ring or urea group were less active when compared with the parent carboline and carbazole derivatives. Optimization studies of a lactam-fused diphenylamine-type KSP inhibitor revealed that the aniline NH group and 3-CF3 phenyl group were indispensable for potent KSP inhibition. Modification with a seven-membered lactam-fused phenyl group and a 4-(trifluoromethyl)pyridin-2-yl group improved aqueous solubility while maintaining potent KSP inhibitory activity. From these studies, we identified novel diaryl amine-type KSP inhibitors with a favorable balance of potency and solubility.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Takeuchi
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. Electronic address: soishi@pharm.kyoto-u.ac.jp.
authors.forename: Shinya
authors.initials: S
authors.lastname: Oishi
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Kaneda
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Misu
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ohno
authors.affiliation: Graduate School of Pharmaceutical Sciences, University of Shizuoka, Suruga-ku, Shizuoka 422-8526, Japan.
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Sawada
authors.affiliation: Graduate School of Pharmaceutical Sciences, University of Shizuoka, Suruga-ku, Shizuoka 422-8526, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Asai
authors.affiliation: Faculty of Pharmacy, Kinki University, 3-4-1 Kowakae, Higashi-osaka 577-8502, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Nakamura
authors.affiliation: Faculty of Pharmacy, Kinki University, 3-4-1 Kowakae, Higashi-osaka 577-8502, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Nakanishi
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. Electronic address: nfujii@pharm.kyoto-u.ac.jp.
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Fujii
mesh_terms: D004159:Diphenylamine / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects*; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D004159:Diphenylamine; D016547:Kinesins
keywords: Aqueous solubility; Diaryl amine; Kinesin spindle protein