Discovery of selective PDE4B inhibitors.
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.
Naganuma
Kenji
K
Pharmaceuticals Research Center, Asahi Kasei Pharma Corporation, 632-1 Mifuku, Izunokuni-shi, Shizuoka 410-2321, Japan.
Omura
Akifumi
A
Maekawara
Naomi
N
Saitoh
Masahiro
M
Ohkawa
Naoto
N
Kubota
Takashi
T
Nagumo
Hiromitsu
H
Kodama
Toshiyuki
T
Takemura
Masayoshi
M
Ohtsuka
Yuji
Y
Nakamura
Junji
J
Tsujita
Ryuichi
R
Kawasaki
Koh
K
Yokoi
Hirotsugu
H
Kawanishi
Masashi
M
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
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