Azasugar-based MMP/ADAM inhibitors as antipsoriatic agents.
As a part of synthetic studies on MMP (matrix metalloproteinase)/ADAM (a disintegrin and metalloproteinase) inhibitors, we have preliminarily communicated that azasugar-based compound 1a exhibited a potential inhibitory activity on some metalloprotease-catalyzed proteolytic reactions. To find promising candidates for the topical treatment of psoriasis, we investigated stability in aqueous solution of compound 1a and its derivative 1b and then optimized the P1' substuent (2-5). In the present study, we synthesized novel derivatives of compound 1a and evaluated their inhibitory activity toward MMP-1, -3, and -9, TACE, and HB-EGF shedding, from a viewpoint of versatility of azasugars as a functional scaffold. As a result, it was found that compound 1b demonstrated desirable inhibitory activity as an antipsoriatic agent, and some of the derivatives showed selective inhibitory activity. In addition, it was found that compound 1b exhibited a significant therapeutic effect on a mouse TPA-induced epidermal hyperplasia model. Therefore, compound 1b could become a promising candidate as a practical antipsoriatic agent.
Moriyama
Hideki
H
Japan Bioindustry Association, Hokkaido Collaboration Center N-21, W-12, Kita-Ku, Sapporo 001-0021, Japan.
Tsukida
Takahiro
T
Inoue
Yoshimasa
Y
Yokota
Kohichi
K
Yoshino
Kohichiro
K
Kondo
Hirosato
H
Miura
Nobuaki
N
Nishimura
Shin-Ichiro
S
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000818:Animals; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002241:Carbohydrates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004195:Disease Models, Animal; D019483:Disintegrins / Q000037:antagonists & inhibitors*; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors; D066257:Heparin-binding EGF-like Growth Factor; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006965:Hyperplasia; D036341:Intercellular Signaling Peptides and Proteins; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors; D051379:Mice; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011565:Psoriasis / Q000188:drug therapy; D012867:Skin / Q000187:drug effects / Q000473:pathology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C485105:3,4,5-trihydroxy-1-(4'-phenoxybenzenesulfonyl)piperidine-2-hydroxy amide; D001372:Aza Compounds; D002241:Carbohydrates; D019483:Disintegrins; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D006877:Hydroxamic Acids; D036341:Intercellular Signaling Peptides and Proteins; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D013450:Sulfones; D004815:Epidermal Growth Factor; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse