title: Identification of the 5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivatives as highly selective PDE4B inhibitors.
abstract: A PDE4B subtype selective inhibitor is expected to have a wider therapeutic window than non-selective PDE4 inhibitors. In this Letter, two series of 7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivatives and 5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivatives were evaluated for their PDE4B subtype selectivity using human PDE4B2 and PDE4D2 full length enzymes. To improve their PDE4B selectivity over PDE4D, we optimized the substituents on the pyrimidine ring and the side chain phenyl ring, resulting in several derivatives with more than 100-fold selectivity for PDE4B. Consequently, we identified 2-(3-chloro-4-methoxy-phenyl)-5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivative 54 as a highly selective PDE4B inhibitor, which had potent hPDE4B inhibitory activity with an IC50 value of 3.0 nM and 433-fold PDE4B selectivity over PDE4D.
authors.affiliation: R&D Division, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan; Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. Electronic address: goto.taiji.kt@daiichisankyo.co.jp.
authors.forename: Taiji
authors.initials: T
authors.lastname: Goto
authors.affiliation: Quality & Safety Management Division, Daiichi Sankyo Co., Ltd, 3-5-1 Nihonbashihoncho, Chuo-ku, Tokyo 103-8426, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Shiina
authors.affiliation: R&D Division, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Murata
authors.affiliation: R&D Division, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Tomii
authors.affiliation: R&D Division, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Yamazaki
authors.affiliation: R&D Division, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: R&D Division, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Yoshino
authors.affiliation: R&D Division, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Suzuki
authors.affiliation: R&D Division, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Sogawa
authors.affiliation: Corporate Strategy Division, Daiichi Sankyo Co., Ltd, 3-5-1 Nihonbashihoncho, Chuo-ku, Tokyo 103-8426, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Mizukami
authors.affiliation: R&D Division, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Nana
authors.initials: N
authors.lastname: Takagi
authors.affiliation: R&D Division, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Yoshitomi
authors.affiliation: R&D Division, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Etori
authors.affiliation: R&D Division, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tsuchida
authors.affiliation: R&D Division, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Mikkaichi
authors.affiliation: R&D Division, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Nakao
authors.affiliation: R&D Division, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Mizuki
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: R&D Division, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Sasaki
mesh_terms: D001665:Binding Sites; D003499:Cyclic S-Oxides / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D010648:Phenylacetates / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D058988:Phosphodiesterase 4 Inhibitors / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*
chemical_list: C000592755:2-(4-((2-(3-chloro-4-methoxyphenyl)-5,5-dioxo-7,8-dihydro-6H-thiopyrano(3,2-d)pyrimidin-4-yl)amino)-2-fluorophenyl)acetic acid; D003499:Cyclic S-Oxides; D004791:Enzyme Inhibitors; D010648:Phenylacetates; D058988:Phosphodiesterase 4 Inhibitors
keywords: COPD; Full length; PDE4; PDE4B; PDE4D; Selective inhibitor