Highly potent PDE4 inhibitors with therapeutic potential

Hiroshi Ochiai, Tazumi Ohtani, Akiharu Ishida, Kensuke Kusumi, Masashi Kato, Hiroshi Kohno, Yoshihiko Odagaki, Katuya Kishikawa, Susumu Yamamoto, Hiroshi Takeda, Takaaki Obata, Hisao Nakai, Masaaki Toda

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)4645-4665
Number of pages21
JournalBioorganic and Medicinal Chemistry
Issue number17
Publication statusPublished - 2004 Sep 1
Externally publishedYes


  • Difluoromethoxy
  • Hydroxamic acid
  • PDE4 inhibitor
  • Pharmacokinetic data
  • Piperidine analog

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry


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