Tetsuya Yabuuchi

Pyrrole derivatives as potent inhibitors of lymphocyte-specific kinase: Structure, synthesis, and SAR

We have described the synthesis, enzyme inhibitory activity, structure-activity relationships, and proposed binding mode of a novel series of pyrrole derivatives as lymphocyte-specific kinase (Lck) inhibitors. The most potent analogs exhibited good enzyme inhibitory activity (IC(50)s <10nM) for Lck kinase inhibition.

Discovery and optimization of a series of 2-aminothiazole-oxazoles as potent phosphoinositide 3-kinase γ inhibitors.

A novel series of 2-aminothiazole-oxazoles was designed and synthesized as part of efforts to develop potent phosphoinositide 3-kinase γ (PI3Kγ) inhibitors. The modification of a high-throughput screening hit, compound 1, resulted in the identification of compounds 10 and 15, which displayed potent inhibitory activities in enzyme-based and cell-based assays.

Discovery of N-{5-[3-(3-hydroxypiperidin-1-yl)-1,2,4-oxadiazol-5-yl]-4-methyl-1,3-thiazol-2-yl}acetamide (TASP0415914) as an orally potent phosphoinositide 3-kinase γ inhibitor for the treatment of inflammatory diseases.

Class I phosphoinositide 3-kinases (PI3Ks), particularly PI3Kγ, have become attractive drug targets for inflammatory and autoimmune disorders such as rheumatoid arthritis. Herein, we describe the synthesis and the structure-activity relationships (SAR) of a series of 2-amino-5-oxadiazolyl thiazoles, culminating in the identification of 8j (TASP0415914), an orally potent inhibitor of phosphoinositide 3-kinase γ (PI3Kγ). TASP0415914 demonstrated good potency in a cell-based assay and, furthermore, exhibited in vivo efficacy in a collagen induced arthritis (CIA) model in mice after oral administration.

Ring-fused pyrazole derivatives as potent inhibitors of lymphocyte-specific kinase (Lck): Structure, synthesis, and SAR.

We have identified a novel series of ring-fused pyrazole derivatives as lymphocyte-specific kinase (Lck) inhibitors. The most potent analogs exhibited good enzyme inhibitory activity (IC(50)s <1nM) as well as excellent cellular activity against mixed lymphocyte reaction (MLR) (IC(50)s <1nM).

The structures and absolute configurations of macrophyllic acids A–E, five new rearranged eudesmane sesquiterpene acids from the bark of Inula macrophylla

Abstract Macrophyllic acids A–E, five novel sesquiterpene acids with a new rearranged carbon skeleton, have been isolated from the bark of Inula macrophylla. Their structures were determined on the basis of spectral evidence (especially by HREIMS and 2D NMR) as well as chemical transformations. The structure of macrophyllic acid A was finally confirmed by an X-ray analysis. The absolute configuration of macrophyllic acid A was determined by appropriate chemical conversion and the means of PGME. The possible biosynthetic pathway for macrophyllic acids A–E is also discussed.

APPLICATION OF PHENYLGLYCINE METHYL ESTER (PGME) TO DETERMINATION OF THE ABSOLUTE CONFIGURATION OF CARBOXYLIC ACIDS HAVING PHENYLALKYL GROUP

(R)- and (S)-phenylglycine methyl ester (PGME) was applied to elucidate the absolute configuration of a series of aliphatic carboxylic acids, 2a and 2b (n = 1–6), which possess a phenyl group on the chain, by the process similar to the modified Moshers method. (S)-PGME was condensed with rac-2a and 2b, and the resulting diastereomeric pair was separated for each of 2a and 2b. Δδ values were calculated from the 1H-NMR chemical shifts of (R)-2a-(or 2b)-(S)-PGME and (R)-2a-(or 2b)-PGME amides. By analyzing the positive and negative distribution patterns for each compound, it was concluded that this new method was successful to predict the absolute configuration of such type of acids, and that no significant interaction between the two phenyl groups, one in the chain and the other in the PGME, was present. Chirality 9:550–555, 1997.

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).