title: Discovery of selective PDE4B inhibitors.
abstract: In this study the first PDE4B selective inhibitor is described. Optimization of lead 2-arylpyrimidine derivatives afforded a series of potent PDE4B inhibitors with >100-fold selectivity over the PDE4D isozyme. With a good pharmacokinetic profile, a selected compound exhibited potent anti-inflammatory effects in vivo and showed less emesis compared with Cilomilast.
authors.affiliation: Pharmaceuticals Research Center, Asahi Kasei Pharma Corporation, 632-1 Mifuku, Izunokuni-shi, Shizuoka 410-2321, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Naganuma
authors.forename: Akifumi
authors.initials: A
authors.lastname: Omura
authors.forename: Naomi
authors.initials: N
authors.lastname: Maekawara
authors.forename: Masahiro
authors.initials: M
authors.lastname: Saitoh
authors.forename: Naoto
authors.initials: N
authors.lastname: Ohkawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Kubota
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Nagumo
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kodama
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Takemura
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ohtsuka
authors.forename: Junji
authors.initials: J
authors.lastname: Nakamura
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Tsujita
authors.forename: Koh
authors.initials: K
authors.lastname: Kawasaki
authors.forename: Hirotsugu
authors.initials: H
authors.lastname: Yokoi
authors.forename: Masashi
authors.initials: M
authors.lastname: Kawanishi
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D019540:Area Under Curve; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism*; D055808:Drug Discovery; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D010648:Phenylacetates / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014839:Vomiting / Q000139:chemically induced
chemical_list: C000621291:2-(4-((2-(5-chlorothiophen-2-yl)-5-ethyl-6-methylpyrimidin-4-yl)amino)phenyl)acetic acid; D000893:Anti-Inflammatory Agents; D010648:Phenylacetates; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors; D011743:Pyrimidines; D013876:Thiophenes; D014409:Tumor Necrosis Factor-alpha; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517360:PDE4B protein, human; C531980:PDE4D protein, mouse