Synthesis and Structure-Activity Relationship of N-Arylrolipram Derivatives as Inhibitors of PDE4 Isozymes

• Published in: Chemical & pharmaceutical bulletin Vol. 49; no. 8; pp. 1009 - 1017
• Main Authors: KELLER, Thomas H., BRAY-FRENCH, Katharine, DEMNITZ, F.W. Joachim, MÜLLER, Thomas, POMBO-VILLAR, Esteban, WALKER, Christoph
• Format: Journal Article
• Language: English
• Published: TOKYO The Pharmaceutical Society of Japan 01.08.2001; Pharmaceutical Soc Japan; Maruzen; Japan Science and Technology Agency
• Subjects: 3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors; 3',5'-Cyclic-AMP Phosphodiesterases - metabolism; Animals; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Brain - metabolism; Chemistry; Chemistry, Medicinal; Chemistry, Multidisciplinary; Cyclic Nucleotide Phosphodiesterases, Type 4; Eosinophils - drug effects; Eosinophils - enzymology; Eosinophils - metabolism; Humans; Isoenzymes - antagonists & inhibitors; Isoenzymes - metabolism; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - metabolism; Life Sciences & Biomedicine; Medical sciences; N-arylrolipram derivative; PDE inhibition; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Phosphodiesterase Inhibitors - chemistry; Phosphodiesterase Inhibitors - pharmacology; Physical Sciences; Rats; Respiratory Burst - drug effects; Respiratory Burst - physiology; Respiratory system; Rolipram; Rolipram - analogs & derivatives; Rolipram - chemistry; Rolipram - pharmacology; rolipram binding; Science & Technology; Stereoisomerism; Structure-Activity Relationship; SITE; (R)-ROLIPRAM; ROLIPRAM ANALOGS; PHOSPHODIESTERASE-IV INHIBITORS; rolipram; N-arylrolipram derivative; AMP-SPECIFIC PHOSPHODIESTERASE; PDE inhibition; rolipram binding; SMOOTH-MUSCLE; POTENT; ASTHMA; MOLECULAR-CLONING; BINDING; Organic hydrazide; 3',5'-Cyclic-nucleotide phosphodiesterase; Enantioselectivity; Ether; Enzyme; Nitrogen heterocycle; Isozyme; Antiinflammatory agent; Benzene derivatives; Lactam; Enzyme inhibitor; Esterases; Selectivity; Phosphoric diester hydrolases; In vitro; Immunomodulator; Structure activity relation; Hydrolases; Chemical synthesis; Cyclopentane derivatives
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.49.1009

Structure activity studies of N-phenylrolipram derivatives have led to the identification of highly potent PDE4 inhibitors. The potential of these inhibitors for cellular activity was routinely assessed in an assay of fMLP induced oxidative burst in human eosinophils. Since first generation PDE4 inhibitors have been plagued with a number of unwanted side effects, parallel structure activity studies for competition with the [3H]-rolipram binding site in rat brain were performed. In this fashion 5-[4-(3-cyclopentyloxy-4-methoxyphenyl)-2-oxo-pyrrolidin-1-yl]-3-(3-methoxybenzyloxy)benzoic acid N',N'-dimethylhydrazide (22) was identified as a potent inhibitor of PDE4 which exhibits >1000 fold selectivity versus PDE3, and is a nanomolar inhibitor in all the cellular assays tested. Studies on the streoselectivity of PDE4 inhibition of this class of rolipram based compounds revealed, that for example (S)-11 is a more potent inhibitor than (R)-11. This effect can also be observed in primary human cells where the (S)-enantiomer is about 10 fold more potent than the corresponding (R)-enantiomer.