title: Design and synthesis of novel 5-(3,4,5-trimethoxybenzoyl)-4-aminopyrimidine derivatives as potent and selective phosphodiesterase 5 inhibitors: scaffold hopping using a pseudo-ring by intramolecular hydrogen bond formation.
abstract: 5-(3,4,5-Trimethoxybenzoyl)-4-amimopyrimidine derivatives were found as a novel chemical class of potent and highly selective phosphodiesterase 5 inhibitors. A pseudo-ring formed by an intramolecular hydrogen bond constrained the conformation of 3-chloro-4-methoxybenzylamino and 3,4,5-trimethoxybenzoyl substituents and led to the discovery of T-6932 (19a) with a potent PDE5 inhibitory activity (IC50 = 0.13 nM) and a high selectivity over PDE6 (IC50 ratio: PDE6/PDE5 = 2400). Further modification at the 2-position of T-6932 resulted in the finding of 26, which exhibited potent relaxant effects on isolated rabbit corpus cavernosum (EC30 = 11 nM) with a high PDE5 selectivity over PDE6 (IC50 ratio: PDE6/PDE5 = 2800).
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: Michino
authors.initials: M
authors.lastname: Murakami
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; D002417:Cattle; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6 / Q000037:antagonists & inhibitors; D004285:Dogs; D015195:Drug Design; D006801:Humans; D006860:Hydrogen Bonding; D058986:Phosphodiesterase 5 Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology; D011817:Rabbits
chemical_list: D058986:Phosphodiesterase 5 Inhibitors; D011743:Pyrimidines; C034821:4-aminopyrimidine; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6
keywords: Erectile dysfunction; Intramolecular hydrogen bond; PDE5; PDE6; Pseudo-ring