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C-Aryl glycoside inhibitors of SGLT2: Exploration of sugar modifications including C-5 spirocyclization
Ralph P Robinson1, Vincent Mascitti, Carine M Boustany-Kari
1Pfizer Global Research & Development, Groton Laboratories Eastern Point Rd, Groton, CT 06340, United States. ralph.p.robinson@pfizer.com
Abstract:
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.
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