Design, Synthesis, and Structure-Activity Relationship, Molecular Modeling, and NMR Studies of a Series of a 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{sub 50} values. The most potent compounds have IC50 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.
- Research Organization:
- Brookhaven National Laboratory (BNL) National Synchrotron Light Source
- Sponsoring Organization:
- Doe - Office Of Science
- DOE Contract Number:
- AC02-98CH10886
- OSTI ID:
- 980137
- Report Number(s):
- BNL--93055-2010-JA
- Journal Information:
- Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 24 Vol. 51; ISSN JMCMAR; ISSN 0022-2623
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
99 GENERAL AND MISCELLANEOUS
AMIDES
AMP
ANTIPYRETICS
ATOMS
CHAINS
DESIGN
FLUORINE
HYDROGEN
HYDROLYSIS
INTERACTIONS
KETONES
NUCLEAR MAGNETIC RESONANCE
PHOSPHODIESTERASES
RANGE
SIMULATION
STRUCTURE-ACTIVITY RELATIONSHIPS
SYNTHESIS
TARGETS
VANS
national synchrotron light source