C-Aryl glycoside inhibitors of SGLT2: Exploration of sugar modifications including C-5 spirocyclization.
Modifications to the sugar portion of C-aryl glycoside sodium glucose transporter 2 (SGLT2) inhibitors were explored, including systematic deletion and modification of each of the glycoside hydroxyl groups. Based on results showing activity to be quite tolerant of structural change at the C-5 position, a series of novel C-5 spiro analogues was prepared. Some of these analogues exhibit low nanomolar potency versus SGLT2 and promote urinary glucose excretion (UGE) in rats. However, due to sub-optimal pharmacokinetic parameters (in particular half-life), predicted human doses did not meet criteria for further advancement.
Pfizer Global Research & Development, Groton Laboratories Eastern Point Rd, Groton, CT 06340, United States. ralph.p.robinson@pfizer.com
Ralph P
RP
Robinson
Vincent
V
Mascitti
Carine M
CM
Boustany-Kari
Christopher L
CL
Carr
Patrick M
PM
Foley
Emi
E
Kimoto
Michael T
MT
Leininger
Andre
A
Lowe
Michelle K
MK
Klenotic
James I
JI
Macdonald
Robert J
RJ
Maguire
Victoria M
VM
Masterson
Tristan S
TS
Maurer
Zhuang
Z
Miao
Jigna D
JD
Patel
Cathy
C
Préville
Matthew R
MR
Reese
Li
L
She
Claire M
CM
Steppan
Benjamin A
BA
Thuma
Tong
T
Zhu
D000818:Animals; D003500:Cyclization; D006027:Glycosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D051297:Sodium-Glucose Transporter 2 / Q000378:metabolism; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013141:Spiro Compounds / Q000737:chemistry*
D006027:Glycosides; D007004:Hypoglycemic Agents; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013141:Spiro Compounds