Development of a Scalable Synthesis of Tofogliflozin.

An efficient and scalable synthesis of an antidiabetic drug, tofogliflozin (1), which was identified as a highly selective sodium glucose cotransporter 2 (SGLT2) inhibitor, is described. A key factor in the synthesis of 1 was the selection of the purpose-designed protecting group, which plays a strategic role in protection, chemoselective activation, and crystalline purification. The developed and optimized method made it possible to prepare 1 on a multidecagram scale without any column chromatography.

Discovery of tofogliflozin, a novel C-arylglucoside with an O-spiroketal ring system, as a highly selective sodium glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes.

Inhibition of sodium glucose cotransporter 2 (SGLT2) has been proposed as a novel therapeutic approach to treat type 2 diabetes. In our efforts to discover novel inhibitors of SGLT2, we first generated a 3D pharmacophore model based on the superposition of known inhibitors. A search of the Cambridge Structural Database using a series of pharmacophore queries led to the discovery of an O-spiroketal C-arylglucoside scaffold. Subsequent chemical examination combined with computational modeling resulted in the identification of the clinical candidate 16d (CSG452, tofogliflozin), which is currently under phase III clinical trials.

C-Aryl 5a-carba-ß-d-glucopyranosides as novel sodium glucose cotransporter 2 (SGLT2) inhibitors for the treatment of type 2 diabetes.

C-Aryl 5a-carba-ß-d-glucopyranose derivatives were synthesized and evaluated for inhibition activity against hSGLT1 and hSGLT2. Modifications to the substituents on the two benzene rings resulted in enhanced hSGLT2 inhibition activity and extremely high hSGLT2 selectivity versus SGLT1. Using the created superimposed model, the reason for the high hSGLT2 selectivity was speculated to be that additional substituents occupied a new space, in a different way than known inhibitors. Among the tested compounds, the ethoxy compound 5h with high hSGLT2 selectivity exhibited more potent and longer hypoglycemic action in db/db mice than our O-carbasugar compound (1) and sergliflozin (2), which could be explained by its improved PK profiles relative to those of the two compounds. These results indicated that 5h might be a promising drug candidate for the treatment of type 2 diabetes.

5a-Carba-ß-D-glucopyranose derivatives as novel sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors for the treatment of type 2 diabetes.

5a-Carba-ß-D-glucopyranose derivatives were synthesized and identified as novel SGLT2-selective inhibitors. These inhibitors exhibited potent SGLT2 inhibition with high selectivity over SGLT1. Among the tested compounds, 6f indicated the most potent hSGLT2 inhibition and the highest selectivity over hSGLT1. Moreover, the pharmacokinetics data also showed that 6h, which had the same aglycon structure as sergliflozin-active (3-active), had a threefold longer half-life time (T(1/2)) than sergliflozin (3) with a high distribution volume in db/db mice. Subsequently, 6h lowered blood glucose levels as much as 3 and showed longer hypoglycemic action than 3 in db/db mice.

Newly discovered orally active pure antiestrogens.

In order to develop orally active pure antiestrogens, we incorporated the carboxy-containing side chains into the 7alpha-position of the steroid scaffold and found that 17-keto derivative CH4893237 (12b) functioned as a pure antiestrogen with its oral activity much superior to clinically used pure antiestrogen, ICI182,780. Results from the pharmacokinetic evaluation indicated that the potent antiestrogen activity at oral dosing in mice attributed to both improved absorption from the intestinal wall and metabolic stability in liver.

Discovery of thiochroman derivatives bearing a carboxy-containing side chain as orally active pure antiestrogens.

In order to search for alternatives to the sulfoxide moiety in the long side chain of pure antiestrogens, several molecules that may interact with water in a fashion similar to ICI164,384 were designed and it was found that compounds with the carboxy, the sulfamide, or the sulfonamide instead of the sulfoxide moiety also functioned as pure antiestrogens. Interestingly, the compound possessing the carboxy moiety showed superior antiestrogen activity compared to ICI182,780 when dosed orally. Results of the pharmacokinetic evaluation indicated that the potent antiestrogen activity at oral dosing attributed to both the improved absorption from the intestinal wall and the metabolic stability of the compound in liver.

Discovery of thiochroman and chroman derivatives as pure antiestrogens and their structure-activity relationship.

In order to develop pure antiestrogens, a series of 7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman and 7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman derivatives with sulfoxide containing side chains at the 4-position were designed, synthesized, and evaluated. Among them, compounds 14b and 24b functioned as pure antiestrogens with the ability to downregulate ER, and their in vitro and in vivo antiestrogen activities were similar to those of ICI182,780. In addition, the structure-activity relationship indicated that the (3RS,4RS)-configuration between the 3- and 4-position, the methyl group at the 3-position, the 9-methylene chain between the scaffold and the sulfoxide moiety, and the terminal perfluoroalkyl moiety play an important role in increasing estrogen receptor binding and oral antiestrogen activities.