Orally active PDE4 inhibitor with therapeutic potential

• Published in: European journal of medicinal chemistry Vol. 39; no. 7; pp. 555 - 571
• Main Authors: Ochiai, Hiroshi, Ohtani, Tazumi, Ishida, Akiharu, Kishikawa, Katuya, Yamamoto, Susumu, Takeda, Hiroshi, Obata, Takaaki, Nakai, Hisao, Toda, Masaaki
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 01.07.2004; Elsevier
• Subjects: 3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors; 3',5'-Cyclic-AMP Phosphodiesterases - metabolism; Administration, Oral; Animals; Bicyclo[3 [formula omitted]3 [formula omitted]0]octane; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Bronchoconstriction - drug effects; Bronchoconstriction - physiology; Chemistry, Medicinal; Cyclic Nucleotide Phosphodiesterases, Type 4; Ferrets; Gastric Emptying - drug effects; Guinea Pigs; Humans; Life Sciences & Biomedicine; Lipopolysaccharides - pharmacology; Male; Medical sciences; Orally active; PDE4 inhibitor; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Phosphodiesterase Inhibitors - chemical synthesis; Phosphodiesterase Inhibitors - pharmacokinetics; Phosphodiesterase Inhibitors - therapeutic use; Rats; Rats, Sprague-Dawley; Science & Technology; Spatial arrangement; Stereoisomerism; Structure-Activity Relationship; Three pharmacophores; Tumor Necrosis Factor-alpha - metabolism; U937 Cells; Orally active; Spatial arrangement; PDE4 inhibitor; Three pharmacophores; Bicyclo[3 ̇ 3 ̇ 0]octane; SITE; ACID; ANTAGONIST; SERIES; three pharmacophores; ALPHA; IV; bicyclo[3 center dot 3 center dot 0] octane; orally active; ASTHMA; spatial arrangement; ANTIINFLAMMATORY DRUGS; PHOSPHODIESTERASE-4; ONO-1078; Nitrile; Intravenous administration; Rat; Isozyme; Saturated compound; Esterases; Selectivity; Phosphoric diester hydrolases; Structure activity relation; PDE4 inhibitor; Bicyclo‖3; 0]octane; Spatial arrangement; Three pharmacophores; Orally active; Bicyclic compound; Inhibition; Chemical synthesis; Tumor necrosis factor α; 3',5'-Cyclic-nucleotide phosphodiesterase; Enzyme; Rodentia; Antiinflammatory agent; Benzene derivatives; Cytokine; Single dose; Oral administration; Hydroxamic acid; Enzyme inhibitor; In vitro; In vivo; Vertebrata; Mammalia; 3; Animal; Hydrolases; Pharmacokinetics
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2004.02.010

Based on the promising results obtained by the clinical trial of Ariflo ™, further optimization of the spatial arrangement of the three pharmacophores (the carboxylic acid moiety, nitrile moiety and 3-cyclopentyloxy-4-methoxyphenyl moiety) in the structure of Ariflo 1 was attempted using a bicyclo[3   ̇ 3   ̇ 0]octane template with more stereochemical diversity than the cyclohexane template of Ariflo 1. Biological evaluation of the decyanated analogs and further optimization of the cyclopentyloxy moiety of 2a–b were also performed. Among the compounds tested, 2a, 7a–b and 12a were found to be orally active and were estimated to have therapeutic potential based on cross-species and same-species comparisons. The structure–activity relationships (SARs) of these compounds were investigated and pharmacokinetic data for 2a and 7b were also obtained by single-dose studies in rats.