Akiko Ikeda

Synthesis and structure-activity relationships of radicicol derivatives and WNT-5A expression inhibitory activity.

WNT-5A, a secretory glycoprotein, is related to the proliferation of dermal papilla cells. To develop a hair-growth stimulant, we have been searching for inhibitors of WNT-5A expression. We identified radicicol (1) as an active compound, and synthesized several radicicol derivatives. Among them, 6,7-dihydro-10alpha-hydroxy radicicol (31) was found to function as a new potent WNT-5A expression inhibitor with relatively low toxicity and excellent stability.

Design, synthesis, and evaluation of novel 4-thiazolylimidazoles as inhibitors of transforming growth factor-β type I receptor kinase.

A novel series of 4-thiazolylimidazoles was synthesized as transforming growth factor-β (TGF-β) type I receptor (also known as activin receptor-like kinase 5 or ALK5) inhibitors. These compounds were evaluated for their ALK5 inhibitory activity in an enzyme assay and their TGF-β-induced Smad2/3 phosphorylation inhibitory activity in a cell-based assay. N-{[5-(1,3-benzothiazol-6-yl)-4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazol-2-yl]methyl}butanamide 20, a potent and selective ALK5 inhibitor, exhibited good enzyme inhibitory activity (IC(50)=8.2nM) as well as inhibitory activity against TGF-β-induced Smad2/3 phosphorylation at a cellular level (IC(50)=32nM).

Novel ALK5 inhibitor TP0427736 reduces TGF-β induced growth inhibition in human outer root sheath cells and elongates anagen phase in mouse hair follicles

BACKGROUND Androgenic alopecia (AGA) occurs as a result of the contraction of the anagen phase because of the action of androgens on hair follicles. TGF-β production from dermal papillae is enhanced by androgens, and growth inhibition of hair-follicle cells is induced by TGF-β, and the hair cycle progresses from the anagen phase to the catagen phase. We investigated both the in vitro and in vivo potency of the newly identified ALK5 inhibitor TP0427736 {6-[4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazol-5-yl]-1,3-benzothiazole}. METHODS For in vitro study, kinase inhibitory activity was evaluated with ELISA, and inhibitory activity against TGF-β-induced Smad2/3 phosphorylation in A549 cells and TGF-β-induced growth inhibition of human outer root sheath cells were assayed using ELISA. For in vivo study, we used a mouse model that had been synchronized through dorsal hair depilation. RESULTS TP0427736 inhibited ALK5 kinase activity with an IC50 of 2.72nM; this effect was 300-fold higher than the inhibitory effect on ALK3. In cell-based assays, TP0427736 inhibited Smad2/3 phosphorylation in A549 cells and decreased the growth inhibition of human outer root sheath cells. The topical application of TP0427736 significantly decreased Smad2 phosphorylation in mouse skin, and its repeated application suppressed the shortening of average hair follicle length during the transition from the late anagen phase to the catagen phase. CONCLUSIONS TP0427736, a potent ALK5 inhibitor with appropriate in vitro and in vivo profiles, may serve as a potential new therapy for AGA.　.BACKGROUND Androgenic alopecia (AGA) occurs as a result of the contraction of the anagen phase because of the action of androgens on hair follicles. TGF-β production from dermal papillae is enhanced by androgens, and growth inhibition of hair-follicle cells is induced by TGF-β, and the hair cycle progresses from the anagen phase to the catagen phase. We investigated both the in vitro and in vivo potency of the newly identified ALK5 inhibitor TP0427736 {6-[4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazol-5-yl]-1,3-benzothiazole}. METHODS For in vitro study, kinase inhibitory activity was evaluated with ELISA, and inhibitory activity against TGF-β-induced Smad2/3 phosphorylation in A549 cells and TGF-β-induced growth inhibition of human outer root sheath cells were assayed using ELISA. For in vivo study, we used a mouse model that had been synchronized through dorsal hair depilation. RESULTS TP0427736 inhibited ALK5 kinase activity with an IC50 of 2.72 nM; this effect was 300-fold higher than the inhibitory effect on ALK3. In cell-based assays, TP0427736 inhibited Smad2/3 phosphorylation in A549 cells and decreased the growth inhibition of human outer root sheath cells. The topical application of TP0427736 significantly decreased Smad2 phosphorylation in mouse skin, and its repeated application suppressed the shortening of average hair follicle length during the transition from the late anagen phase to the catagen phase. CONCLUSIONS TP0427736, a potent ALK5 inhibitor with appropriate in vitro and in vivo profiles, may serve as a potential new therapy for AGA.　.

5-(1,3-Benzothiazol-6-yl)-4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazole derivatives as potent and selective transforming growth factor-β type I receptor inhibitors

A series of 5-(1,3-benzothiazol-6-yl)-4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazole derivatives was synthesized as transforming growth factor-β (TGF-β) type I receptor (also known as activin-like kinase 5 or ALK5) inhibitors. These compounds were evaluated for their ALK5 inhibitory activity in an enzyme assay and for their TGF-β-induced Smad2/3 phosphorylation inhibitory activity in a cell-based assay. As a representative compound, 16i was a potent and selective ALK5 inhibitor, exhibiting a good enzyme inhibitory activity (IC(50) = 5.5 nM) as well as inhibitory activity against TGF-β-induced Smad2/3 phosphorylation at a cellular level (IC(50) = 36 nM). Furthermore, the topical application of 3% 16i lotion significantly inhibited Smad2 phosphorylation in Mouse skin (90% inhibition compared with vehicle-treated animals).

13-BROMOMONOCILLIN I: A NEW WNT-5A EXPRESSION INHIBITOR PRODUCED BY POCHONIA CHLAMYDOSPORIA VAR. CHLAMYDOSPORIA

WNT-5A is a secretory glycoprotein related to the proliferation of dermal papilla cells. While searching for an inhibitor of WNT-5A expression, a new compound, 13-bromomonocillin I (1), was isolated from the fermentation broth of the fungus Pochonia chlamydosporia, cultured in NaBr-supplemented medium. 13-Bromomonocillin I (1) exhibited WNT-5A expression inhibitory activity with an IC 50 value of 0.25 μM.

Bone Resorption Is Inhibited by an Osteocyte-Derived Protein

In the process of bone resorption, osteoclasts encounter a large number of osteocytes excavated from the bone tissue. For instance, osteocytes released from the collagen matrix have been shown to be engulfed into osteoclasts by phagocytosis. After the osteoclast-osteocyte encounter or incorporation of osteocytes into osteoclasts, it is possible that osteocytes transmit some signals to osteoclasts.