1. Synthesis and structure-activity relationships of 5,6,7,8-tetrahydropyrido[3,4-b]pyrazine-based hydroxamic acids as HB-EGF shedding inhibitors.
- Author
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Yoshiizumi K, Yamamoto M, Miyasaka T, Ito Y, Kumihara H, Sawa M, Kiyoi T, Yamamoto T, Nakajima F, Hirayama R, Kondo H, Ishibushi E, Ohmoto H, Inoue Y, and Yoshino K
- Subjects
- Heparin-binding EGF-like Growth Factor, Humans, Hydroxamic Acids chemical synthesis, Intercellular Signaling Peptides and Proteins, Protease Inhibitors chemistry, Protease Inhibitors pharmacology, Pyrazines chemical synthesis, Stereoisomerism, Structure-Activity Relationship, Sulfonamides chemical synthesis, Sulfonamides chemistry, Sulfonamides pharmacology, Tumor Cells, Cultured, Epidermal Growth Factor antagonists & inhibitors, Hydroxamic Acids chemistry, Hydroxamic Acids pharmacology, Pyrazines chemistry, Pyrazines pharmacology
- 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 existence 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.
- Published
- 2003
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