Discovery of selective PDE4B inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 19; no. 12; pp. 3174 - 3176
• Main Authors: NAGANUMA, Kenji, OMURA, Akifumi, NAKAMURA, Junji, TSUJITA, Ryuichi, KAWASAKI, Koh, YOKOI, Hirotsugu, KAWANISHI, Masashi, MAEKAWARA, Naomi, SAITOH, Masahiro, OHKAWA, Naoto, KUBOTA, Takashi, NAGUMO, Hiromitsu, KODAMA, Toshiyuki, TAKEMURA, Masayoshi, OHTSUKA, Yuji
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier 15.06.2009
• Subjects: Animals; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - pharmacokinetics; Anti-Inflammatory Agents - pharmacology; Area Under Curve; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Cyclic Nucleotide Phosphodiesterases, Type 4 - metabolism; Drug Discovery; Humans; Inhibitory Concentration 50; Medical sciences; Mice; Pharmacology. Drug treatments; Phenylacetates - chemistry; Phenylacetates - pharmacokinetics; Phenylacetates - pharmacology; Phosphodiesterase 4 Inhibitors; Phosphodiesterase Inhibitors - chemistry; Phosphodiesterase Inhibitors - pharmacokinetics; Phosphodiesterase Inhibitors - pharmacology; Pyrimidines - chemistry; Pyrimidines - pharmacokinetics; Pyrimidines - pharmacology; Structure-Activity Relationship; Thiophenes - chemistry; Thiophenes - pharmacokinetics; Thiophenes - pharmacology; Tumor Necrosis Factor-alpha - biosynthesis; Vomiting - chemically induced; Isozyme; Toxicity; Esterases; Selectivity; Phosphoric diester hydrolases; Benzoic acid derivatives; Thiophene derivatives; Structure activity relation; Vomiting; PDE4B; Fissipedia; Carnivora; Enzyme; Rodentia; Oral administration; Cilomilast; In vitro; In vivo; Vertebrata; Mammalia; Mouse; Aminoacid; Animal; Ferret; Neutrophilia; 2-Arylpyrimidine; Hydrolases; Digestive diseases; Pyrimidine derivatives; Inhibitor; Neutrophil; Pharmacokinetics
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.04.121

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.