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Discovery of a potent,low-absorbable sodium-dependent glucose cotransporter 1 (SGLT1) inhibitor (TP0438836) for the treatment of type 2 diabetes |
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| Authors: | Shoichi Kuroda Yohei Kobashi Takahiro Oi Hideaki Amada Lisa Okumura-Kitajima Fusayo Io Koji Yamamto Hiroyuki Kakinuma |
| Affiliation: | 1. Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan;2. Pharmaceutical Science Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan;3. Development Management, Taisho Pharmaceutical Co., Ltd., 3-24-1, Takada, Toshima-ku, Tokyo 170-8633, Japan;4. Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan;5. Medical Affairs Group, Taisho Toyama Pharmaceutical Co., 3-25-1, Takada, Toshima-ku, Tokyo 170-8635, Japan |
| Abstract: | The design and synthesis of a novel class of low-absorbable SGLT1 inhibitors are described. To achieve low absorption in the new series, we performed an optimization study based on a strategy to increase TPSA. Fortunately, the optimization of an aglycon moiety and a side chain of the distal aglycon moiety led to the identification of compound 30b as a potent and low-absorbable SGLT1 inhibitor. Compound 30b showed a desirable PK profile in Sprague-Dawley (SD) rats and a favorable glucose-lowering effect in diabetic rats. |
| Keywords: | Diabetes SGLT1 SGLT1 inhibitor TPSA Low-absorbable |
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