Design, synthesis, and biological evaluation of new phosphodiesterase type 4 inhibitors.
The design, synthesis, and biological evaluation of new phosphodiesterase type 4 inhibitors, which possess new templates instead of a cyclohexane ring, are described. The mode of interaction with the enzyme is discussed based on the structure-activity relationship (SAR) data obtained for the synthesized inhibitors. Furthermore, the roles of three pharmacophores, a catechol moiety, a nitrile moiety, and acidic moieties, are discussed using in silico docking studies. More detailed biological evaluations of selected compounds are also presented.
Ochiai
Hiroshi
H
Minase Research Institute, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan.
Odagaki
Yoshihiko
Y
Ohtani
Tazumi
T
Ishida
Akiharu
A
Kusumi
Kensuke
K
Kishikawa
Katuya
K
Yamamoto
Susumu
S
Takeda
Hiroshi
H
Obata
Takaaki
T
Kobayashi
Kaoru
K
Nakai
Hisao
H
Toda
Masaaki
M
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D001665:Binding Sites; D016084:Bronchoconstriction / Q000187:drug effects; D003198:Computer Simulation; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005289:Ferrets; D005746:Gastric Emptying / Q000187:drug effects; D006168:Guinea Pigs; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D020889:Rolipram / Q000737:chemistry; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D014839:Vomiting / Q000188:drug therapy
D004791:Enzyme Inhibitors; D006576:Heterocyclic Compounds, 4 or More Rings; D014409:Tumor Necrosis Factor-alpha; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram