Discovery of a potent, low-absorbable sodium-dependent glucose cotransporter 1 (SGLT1) inhibitor (TP0438836) for the treatment of type 2 diabetes

Shoichi Kuroda; Yohei Kobashi; Takahiro Oi; Hideaki Amada; Lisa Okumura-Kitajima; Fusayo Io; Koji Yamamto; Hiroyuki Kakinuma

doi:10.1016/j.bmcl.2018.09.035

Discovery of a potent, low-absorbable sodium-dependent glucose cotransporter 1 (SGLT1) inhibitor (TP0438836) for the treatment of type 2 diabetes

Bioorg Med Chem Lett. 2018 Dec 1;28(22):3534-3539. doi: 10.1016/j.bmcl.2018.09.035. Epub 2018 Sep 29.

Authors

Shoichi Kuroda¹, Yohei Kobashi², Takahiro Oi³, Hideaki Amada⁴, Lisa Okumura-Kitajima⁵, Fusayo Io⁶, Koji Yamamto⁵, Hiroyuki Kakinuma⁷

Affiliations

¹ Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan. Electronic address: s-kuroda@taisho.co.jp.
² Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan.
³ Pharmaceutical Science Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan.
⁴ Development Management, Taisho Pharmaceutical Co., Ltd., 3-24-1, Takada, Toshima-ku, Tokyo 170-8633, Japan.
⁵ Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan.
⁶ Medical Affairs Group, Taisho Toyama Pharmaceutical Co., 3-25-1, Takada, Toshima-ku, Tokyo 170-8635, Japan.
⁷ Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan. Electronic address: h-kakinuma@taisho.co.jp.

PMID: 30297284
DOI: 10.1016/j.bmcl.2018.09.035

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; Low-absorbable; SGLT1; SGLT1 inhibitor; TPSA.

MeSH terms

Animals
Blood Glucose / analysis
Diabetes Mellitus, Experimental / drug therapy
Diabetes Mellitus, Experimental / pathology
Drug Evaluation, Preclinical
Half-Life
Humans
Hypoglycemic Agents / chemistry*
Hypoglycemic Agents / pharmacokinetics
Hypoglycemic Agents / therapeutic use
Inhibitory Concentration 50
Rats
Rats, Sprague-Dawley
Sodium-Glucose Transporter 1 / antagonists & inhibitors*
Sodium-Glucose Transporter 1 / metabolism
Sodium-Glucose Transporter 2 / chemistry
Sodium-Glucose Transporter 2 / metabolism
Structure-Activity Relationship

Substances

Blood Glucose
Hypoglycemic Agents
Sodium-Glucose Transporter 1
Sodium-Glucose Transporter 2