Design, synthesis, and structure-activity relationship, molecular modeling, and NMR studies of a series of phenyl alkyl ketones as highly potent and selective phosphodiesterase-4 inhibitors.
Phosphodiesterase 4 catalyzes the hydrolysis of cyclic AMP and is a target for the development of anti-inflammatory agents. We have designed and synthesized a series of phenyl alkyl ketones as PDE4 inhibitors. Among them, 13 compounds were identified as having submicromolar IC(50) values. The most potent compounds have IC(50) values of in the mid- to low-nanomolar range. Compound 5v also showed preference for PDE4 with selectivity of >2000-fold over PDE7, PDE9, PDE2, and PDE5. Docking of 5v, 5zf, and 5za into the binding pocket of the PDE4 catalytic domain revealed a similar binding profile to PDE4 with rolipram except that the fluorine atoms of the difluoromethyl groups of 5v, 5za, and 5zf are within a reasonable range for hydrogen bond formation with the amide hydrogen of Thr 333 and the long alkyl chain bears additional van der Waals interactions with His 160, Asp 318, and Tyr 159.
Zheng
Shilong
S
Department of Chemistry and Center for Biotechnology and Drug Discovery, Georgia State University, Atlanta, Georgia 30302-4098, USA.
Kaur
Gurpreet
G
Wang
Huanchen
H
Li
Minyong
M
Macnaughtan
Megan
M
Yang
Xiaochuan
X
Reid
Suazette
S
Prestegard
James
J
Wang
Binghe
B
Ke
Hengming
H
D002626:Chemistry, Pharmaceutical / Q000295:instrumentation / Q000379:methods*; D018360:Crystallography, X-Ray / Q000379:methods; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000737:chemistry; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007659:Ketones / Q000737:chemistry*; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D058988:Phosphodiesterase 4 Inhibitors; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D007659:Ketones; D058988:Phosphodiesterase 4 Inhibitors; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4