Hiroo Koyama

A novel synthetic approach toward the zaragozic acids core structure

Abstract A novel synthetic approach toward the zaragozic acids core structure is described. New dipolarophiles in the 1,3-dipolar cycloaddition to the carbonyl ylides are reported. The substituent effect of the dipolarophiles is also discussed.

Aryloxazolidinediones: identification of potent orally active PPAR dual α/γ agonists

Abstract A series of novel aryloxazolidine-2,4-diones was synthesized. A structure–activity relationship study of these compounds led to the identification of potent, orally active PPAR dual α/γ agonists. Based on the results of efficacy studies in the db/db mice model of type 2 diabetes and the desired pharmacokinetic parameters, compound 12 was selected for further profiling.

5-Aryl thiazolidine-2,4-diones as selective PPARγ agonists

A series of 5-aryl thiazolidine-2,4-diones containing 4-phenoxyphenyl side chains was designed, synthesized, and evaluated for PPAR agonist activities. One such compound 28 exhibited comparable levels of glucose correction to rosiglitazone in the db/db mouse type 2 diabetes animal model.

Activity cliff for 7-substituted pyrrolo-pyrimidine inhibitors of HCK explained in terms of predicted basicity of the amine nitrogen.

We previously reported the structure-based design of a highly potent hematopoietic cell kinase (HCK) inhibitor, a pyrrolo-pyrimidine compound designated RK-20449, for treatment of recurrent leukemia. Herein we report the synthesis and structure-activity relationships of some amino acid derivatives of 7-substituted pyrrolo-pyrimidine. Although these derivatives had the same predicted binding conformation as RK-20449, their IC50 values were 100-1000 times larger than that of the parent compound. We assumed that the basicity of the amine nitrogen, which formed an ionic bond with Asp348 of HCK, markedly affected inhibitory activity against HCK. The pKa values of the nitrogen were predicted by means of an ab initio quantum mechanical method, and complexes of the derivatives with HCK were analyzed by X-ray crystallography. We observed a significant correlation between the predicted pKa and IC50 values, and the crystal structures of the less potent derivatives showed various types of defects around the ionic bond.

Identification of pyrrolo[2,3-d]pyrimidines as potent HCK and FLT3-ITD dual inhibitors

A series of novel pyrrolo[2,3-d]pyrimidines were synthesized by introducing 15 different amino acids to 7-cyclohexyl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine. Compounds with potent activities against HCK and FLT3-ITD were evaluated in viability studies with acute myeloid leukemia cell line MV4-11. Our structure activity relationship analyses lead to the identification of compound 31, which exhibited potent HCK and FLT3-ITD inhibition and activity against the MV4-11 cell line.