Kosuke Yasuda

SAR, Pharmacokinetics, Safety, and Efficacy of Glucokinase Activating 2-(4-Sulfonylphenyl)-N-thiazol-2-ylacetamides : Discovery of PSN-GK1

Allosteric activators of the glucose-sensing enzyme glucokinase (GK) are currently attracting much interest as potential antidiabetic therapies because they can achieve powerful blood glucose lowering through actions in multiple organs. Here, the optimization of a weakly active high-throughput screening hit to (2 R)-2-(4-cyclopropanesulfonylphenyl)- N-(5-fluorothiazol-2-yl)-3-(tetrahydropyran-4-yl)propionamide (PSN-GK1), a potent GK activator with an improved pharmacokinetic and safety profile, is described. Following oral administration, this compound elicited robust glucose lowering in rats.

Modifications and structure–activity relationships at the 2-position of 4-sulfonamidopyrimidine derivatives as potent endothelin antagonists

To improve water solubility and to study structure-activity relationships, we modified the structure of the pyrimidine nucleus of each of a series of potent ET(A) antagonists, 3a and 4a, at the 2-position. In a previous study, each of these antagonists showed an extremely high affinity for the ET(A) receptor in porcine aortic membrane (IC(50) 3a; < 0.001 nM, 4a; 0.0039 nM). Two modification methods, one being the addition of organolithium followed by DDQ oxidation and the other being the nucleophilic substitution of 2-(methylsulfonyl)pyrimidine, were applied individually to synthesize 2-substituted-4-sulfonamidopyrimidine derivatives. The introduction of aryl, heteroaryl, alkyl, amino, alkoxy, or alkylthio groups into the 2-position varied the affinity. Derivatives with hydrophilic groups at the 2-position showed higher water solubility but tended to reduce the affinity for the ET(A) receptor.

Design, syntheses, and structure–Activity relationships of indan derivatives as endothelin antagonists; new lead generation of non-peptidic antagonist from peptidic leads

A new lead generation of non-peptidic ET(A) antagonists from two peptidic ET(A)-selective ones, BQ-123 and FR139317, was performed. Using computer assisted molecular modeling, a putative pharmacophore was constructed from the superposition of the reported three-dimensional structure of the cyclic peptide BQ-123 and a presumable beta-turn active conformation of the linear peptide FR139317 formed by an intramolecular hydrogen bond. According to this model, a new series of indan derivatives were designed and synthesized. Among these, 5-isobutyrylamino-6-(1-naphthylmethyloxy)-3-(2-thienyl)-1-indancarboxylic acid (1b) showed a moderate ET(A) antagonistic activity (IC50 = 28 microM).