title: Highly potent PDE4 inhibitors with therapeutic potential.
abstract: 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.
authors.affiliation: Minase Research Institute, Ono Pharmaceutical Co. Ltd., 3-1-1 Sakurai, Shimamoto, Osaka, Mishima 618-8585, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ochiai
authors.forename: Tazumi
authors.initials: T
authors.lastname: Ohtani
authors.forename: Akiharu
authors.initials: A
authors.lastname: Ishida
authors.forename: Kensuke
authors.initials: K
authors.lastname: Kusumi
authors.forename: Masashi
authors.initials: M
authors.lastname: Kato
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kohno
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Odagaki
authors.forename: Katuya
authors.initials: K
authors.lastname: Kishikawa
authors.forename: Susumu
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takeda
authors.forename: Takaaki
authors.initials: T
authors.lastname: Obata
authors.forename: Hisao
authors.initials: H
authors.lastname: Nakai
authors.forename: Masaaki
authors.initials: M
authors.lastname: Toda
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000085:Acetates / Q000737:chemistry; D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002614:Chelating Agents / Q000138:chemical synthesis / Q000627:therapeutic use; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D003509:Cyclohexanecarboxylic Acids / Q000737:chemistry; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry; D007536:Isomerism; D009570:Nitriles; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000085:Acetates; D000893:Anti-Inflammatory Agents; D002614:Chelating Agents; D003509:Cyclohexanecarboxylic Acids; D006877:Hydroxamic Acids; D009570:Nitriles; D010726:Phosphodiesterase Inhibitors; D011725:Pyridines; C055934:difluoromethoxyacetic acid; C433247:Cilomilast; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4