Synthesis and structure-activity relationships of 5,6,7,8-tetrahydropyrido[3,4-b]pyrazine-based hydroxamic acids as HB-EGF shedding inhibitors.
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.
Yoshiizumi
Kazuya
K
R&D Laboratories, Nippon Organon K.K., 1-5-90, Tomobuchi-cho, Miyakojima-ku, Osaka 534-0016, Japan. k.yoshiizumi@organon.nhe.akzonobel.nl
Yamamoto
Minoru
M
Miyasaka
Tomohiro
T
Ito
Yasuko
Y
Kumihara
Hiroshi
H
Sawa
Masaaki
M
Kiyoi
Takao
T
Yamamoto
Takeshi
T
Nakajima
Fumio
F
Hirayama
Ryoichi
R
Kondo
Hirosato
H
Ishibushi
Etsuko
E
Ohmoto
Hiroshi
H
Inoue
Yoshimasa
Y
Yoshino
Kohichiro
K
D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors*; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D036341:Intercellular Signaling Peptides and Proteins; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014407:Tumor Cells, Cultured
C097658:CGS 27023A; C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D006877:Hydroxamic Acids; D036341:Intercellular Signaling Peptides and Proteins; D011480:Protease Inhibitors; D011719:Pyrazines; D013449:Sulfonamides; D004815:Epidermal Growth Factor