Structure-activity relationship studies of 4-benzyl-1H-pyrazol-3-yl β-d-glucopyranoside derivatives as potent and selective sodium glucose co-transporter 1 (SGLT1) inhibitors with therapeutic activity on postprandial hyperglycemia.
Sodium glucose co-transporter 1 (SGLT1) plays a dominant role in the absorption of glucose in the gut and is considered a promising target in the development of treatments for postprandial hyperglycemia. A series of 4-benzyl-1H-pyrazol-3-yl β-d-glucopyranoside derivatives have been synthesized, and its inhibitory activity toward SGLTs has been evaluated. By altering the substitution groups at the 5-position of the pyrazole ring, and every position of the phenyl ring, we studied the structure-activity relationship (SAR) profiles and identified a series of potent and selective SGLT1 inhibitors. Representative derivatives showed a dose-dependent suppressing effect on the escalation of blood glucose levels in oral mixed carbohydrate tolerance tests (OCTT) in streptozotocin-nicotinamide-induced diabetic rats (NA-STZ rats).
Central Research Laboratory, Kissei Pharmaceutical Company, 4365-1 Kashiwabara, Hotaka, Azumino, Nagano Prefecture, Japan. nobuhiko_fushimi@pharm.kissei.co.jp
Nobuhiko
N
Fushimi
Hideki
H
Fujikura
Hiroaki
H
Shiohara
Hirotaka
H
Teranishi
Kazuo
K
Shimizu
Shigeru
S
Yonekubo
Kohsuke
K
Ohno
Takashi
T
Miyagi
Fumiaki
F
Itoh
Toshihide
T
Shibazaki
Masaki
M
Tomae
Yukiko
Y
Ishikawa-Takemura
Takeshi
T
Nakabayashi
Noboru
N
Kamada
Tomonaga
T
Ozawa
Susumu
S
Kobayashi
Masayuki
M
Isaji
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D018360:Crystallography, X-Ray; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D005960:Glucosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D008968:Molecular Conformation; D051381:Rats; D051269:Sodium-Glucose Transporter 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051297:Sodium-Glucose Transporter 2 / Q000378:metabolism; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013329:Structure-Activity Relationship
D001786:Blood Glucose; D005960:Glucosides; D007004:Hypoglycemic Agents; D051269:Sodium-Glucose Transporter 1; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C410942:benzyl glucopyranoside