Highly potent PDE4 inhibitors with therapeutic potential

• Published in: Bioorganic & medicinal chemistry 2004-09, Vol.12 (17), p.4645-4665
• Main Authors: Ochiai, Hiroshi, Ohtani, Tazumi, Ishida, Akiharu, Kusumi, Kensuke, Kato, Masashi, Kohno, Hiroshi, Odagaki, Yoshihiko, Kishikawa, Katuya, Yamamoto, Susumu, Takeda, Hiroshi, Obata, Takaaki, Nakai, Hisao, Toda, Masaaki
• Format: Article
• Language: English
• Subjects: 3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors; Acetates - chemistry; Administration, Oral; Animals; Anti-Inflammatory Agents - pharmacology; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Chelating Agents - chemical synthesis; Chelating Agents - therapeutic use; Cyclic Nucleotide Phosphodiesterases, Type 4; Cyclohexanecarboxylic Acids - chemistry; Difluoromethoxy; Humans; Hydroxamic acid; Hydroxamic Acids - chemistry; Isomerism; Medical sciences; Nitriles; PDE4 inhibitor; Pharmacokinetic data; Pharmacology. Drug treatments; Phosphodiesterase Inhibitors - chemical synthesis; Phosphodiesterase Inhibitors - pharmacology; Piperidine analog; Pyridines - chemical synthesis; Pyridines - pharmacology; Rats; Structure-Activity Relationship
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2004.06.032

Synthesis and biological evaluation of piperidine derivatives is reported. The hypothesis that the dose-limiting side effects of PDE4 inhibitors could be mediated via the central nervous system prompted us to design and synthesize a hydrophilic piperidine analog to improve the side effect profile of Ariflo™ 1, which is an orally active second-generation PDE4 inhibitor. During evaluation of various water-soluble piperidine analogs, 2a– b, 11b– 14b, and 17a showed therapeutic potential in cross-species comparison studies. The following three findings were obtained: (1) The hydroxamic acid group, a well known metal chelator, caused a marked increase of inhibitory activity. (2) Water-soluble piperidine analogs lacked the configurational isomerism of Ariflo 1 without loss of inhibitory activity. (3) Replacement of the 4-methoxy residue with a difluoromethoxy residue led to an increase of in vivo potency. Structure–activity relationships are presented. Single-dose rat pharmacokinetic data for 11b, 12b, and 17a are also presented.