Synthesis and structure-activity relationships of 5,6,7,8-tetrahydropyrido[3,4-b]pyrazine-based hydroxamic acids as HB-EGF shedding inhibitors

Kazuya Yoshiizumi, Minoru Yamamoto, Tomohiro Miyasaka, Yasuko Ito, Hiroshi Kumihara, Masaaki Sawa, Takao Kiyoi, Takeshi Yamamoto, Fumio Nakajima, Ryoichi Hirayama, Hirosato Kondo, Etsuko Ishibushi, Hiroshi Ohmoto, Yoshimasa Inoue, Kohichiro Yoshino

Research output: Contribution to journalArticlepeer-review

21 Citations (Scopus)

Abstract

HB-EGF Shedding inhibitors have been expected to become effective medicines for skin diseases caused by the proliferation of keratinocytes. In order to discover novel HB-EGF shedding inhibitors and clarify their structure-activity relationships, 5,6,7,8-tetrahydronaphthylidine-based hydroxamic acid and 5,6,7,8-tetrahydropyrido[3,4-b]pyrazine-based hydroxamic acids have been synthesized. Among the synthesized compounds, the ethoxyethoxy derivative 3o and the methoxypropoxy derivative 3p exhibited much more potent HB-EGF shedding inhibitory activity than CGS 27023A. The structural modification of 5,6,7,8-tetrahydropyrido[3,4-b]pyrazine-based hydroxamic acids enabled us to establish the following structure-activity relationships; the existences of the hydroxamic acid, the sulfonamide, and the phenyl moieties are crucial for a potent HB-EGF shedding inhibitory activity, and the stereochemistry of the alpha carbon of hydroxamic acid is also important. In addition, from the comparison of their HB-EGF shedding inhibitory activities with their MMPs inhibitory activities, we found that the S1′ pocket of the responsible enzyme for HB-EGF shedding is deep unlike that of MMP-1.

Original languageEnglish
Pages (from-to)433-450
Number of pages18
JournalBioorganic and Medicinal Chemistry
Volume11
Issue number3
DOIs
Publication statusPublished - Feb 1 2003
Externally publishedYes

All Science Journal Classification (ASJC) codes

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

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