title: 8-(3-chloro-4-methoxybenzyl)-8H-pyrido[2,3-d]pyrimidin-7-one derivatives as potent and selective phosphodiesterase 5 inhibitors.
abstract: A novel series of highly selective phosphodiesterase 5 (PDE5) inhibitors was found. 8H-Pyrido[2,3-d]pyrimidin-7-one derivatives bearing an (S)-2-(hydroxymethyl)pyrrolidin-1-yl group at the 2-position and a 3-chloro-4-methoxybenzyl group at the 8-position exhibited potent PDE5 inhibitory activities and high PDE5 selectivity over PDE6. Among the synthesized compounds, the 5-methyl analogue (5b) showed the most potent relaxant effect on isolated rabbit corpus cavernosum with an EC30 value of 0.85 nM.
authors.affiliation: Medicinal Chemistry Research Laboratories II, Mitsubishi Tanabe Pharma Corporation, 2-2-50 Kawagishi, Toda, Saitama 335-8505, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Sakamoto
authors.affiliation: Medicinal Chemistry Research Laboratories II, Mitsubishi Tanabe Pharma Corporation, 2-2-50 Kawagishi, Toda, Saitama 335-8505, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Koga
authors.affiliation: Medicinal Chemistry Research Laboratories II, Mitsubishi Tanabe Pharma Corporation, 2-2-50 Kawagishi, Toda, Saitama 335-8505, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Hikota
authors.affiliation: Medicinal Chemistry Research Laboratories II, Mitsubishi Tanabe Pharma Corporation, 2-2-50 Kawagishi, Toda, Saitama 335-8505, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Matsuki
authors.affiliation: Pharmacology Research Laboratories II, Mitsubishi Tanabe Pharma Corporation, 2-2-50 Kawagishi, Toda, Saitama 335-8505, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Mochida
authors.affiliation: Pharmacology Research Laboratories II, Mitsubishi Tanabe Pharma Corporation, 2-2-50 Kawagishi, Toda, Saitama 335-8505, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Kikkawa
authors.affiliation: Advanced Medical Research Laboratories, Mitsubishi Tanabe Pharma Corporation, 2-2-50 Kawagishi, Toda, Saitama 335-8505, Japan.
authors.forename: Kotomi
authors.initials: K
authors.lastname: Fujishige
authors.affiliation: Advanced Medical Research Laboratories, Mitsubishi Tanabe Pharma Corporation, 2-2-50 Kawagishi, Toda, Saitama 335-8505, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Kotera
authors.affiliation: Advanced Medical Research Laboratories, Mitsubishi Tanabe Pharma Corporation, 2-2-50 Kawagishi, Toda, Saitama 335-8505, Japan; Industry and Academia Cooperation Research Project, Laboratory of Target and Drug Discovery, Graduate School of Pharmaceutical Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Omori
authors.affiliation: Medicinal Chemistry Research Laboratories II, Mitsubishi Tanabe Pharma Corporation, 2-2-50 Kawagishi, Toda, Saitama 335-8505, Japan. Electronic address: morimoto.hiroshi@md.mt-pharma.co.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Morimoto
authors.affiliation: Medicinal Chemistry Research Laboratories II, Mitsubishi Tanabe Pharma Corporation, 2-2-50 Kawagishi, Toda, Saitama 335-8505, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Yamada
mesh_terms: D000818:Animals; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015394:Molecular Structure; D058986:Phosphodiesterase 5 Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits; D013329:Structure-Activity Relationship
chemical_list: D058986:Phosphodiesterase 5 Inhibitors; D011728:Pyridones; D011743:Pyrimidines; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5
keywords: Erectile dysfunction; PDE5; PDE6