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Highly potent PDE4 inhibitors with therapeutic potential.
Bioorg Med Chem 2004; 12(17):4645-65BM

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+Show Affiliations

Minase Research Institute, Ono Pharmaceutical Co. Ltd., 3-1-1 Sakurai, Shimamoto, Osaka, Mishima 618-8585, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article

Language

eng

PubMed ID

15358291

Citation

Ochiai, Hiroshi, et al. "Highly Potent PDE4 Inhibitors With Therapeutic Potential." Bioorganic & Medicinal Chemistry, vol. 12, no. 17, 2004, pp. 4645-65.
Ochiai H, Ohtani T, Ishida A, et al. Highly potent PDE4 inhibitors with therapeutic potential. Bioorg Med Chem. 2004;12(17):4645-65.
Ochiai, H., Ohtani, T., Ishida, A., Kusumi, K., Kato, M., Kohno, H., ... Toda, M. (2004). Highly potent PDE4 inhibitors with therapeutic potential. Bioorganic & Medicinal Chemistry, 12(17), pp. 4645-65.
Ochiai H, et al. Highly Potent PDE4 Inhibitors With Therapeutic Potential. Bioorg Med Chem. 2004 Sep 1;12(17):4645-65. PubMed PMID: 15358291.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Highly potent PDE4 inhibitors with therapeutic potential. AU - Ochiai,Hiroshi, AU - Ohtani,Tazumi, AU - Ishida,Akiharu, AU - Kusumi,Kensuke, AU - Kato,Masashi, AU - Kohno,Hiroshi, AU - Odagaki,Yoshihiko, AU - Kishikawa,Katuya, AU - Yamamoto,Susumu, AU - Takeda,Hiroshi, AU - Obata,Takaaki, AU - Nakai,Hisao, AU - Toda,Masaaki, PY - 2004/05/29/received PY - 2004/06/23/revised PY - 2004/06/23/accepted PY - 2004/9/11/pubmed PY - 2005/8/16/medline PY - 2004/9/11/entrez SP - 4645 EP - 65 JF - Bioorganic & medicinal chemistry JO - Bioorg. Med. Chem. VL - 12 IS - 17 N2 - 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. SN - 0968-0896 UR - https://www.unboundmedicine.com/medline/citation/15358291/Highly_potent_PDE4_inhibitors_with_therapeutic_potential_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0968-0896(04)00477-8 DB - PRIME DP - Unbound Medicine ER -