Glycosylated dihydrochalcones as potent and selective sodium glucose co-transporter 2 (SGLT2) inhibitors.
A series of glucose conjugates was synthesized and tested for inhibition of SGLT1 and SGLT2. The core structure was derived from compound 1a. Modification of the benzofuran moiety and 4'-substituent of the phenyl ring in compound 1a improved selectivity at SGLT2. Select compounds were compared to 1a in metabolic stability and in vivo efficacy studies.
Dudash
Joseph
J
Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 1000 Rt. 202, PO Box 300, Raritan, NJ 08869, USA. jdudash@prdus.jnj.com
Zhang
Xiaoyan
X
Zeck
Roxanne E
RE
Johnson
Sigmond G
SG
Cox
Geoffrey G
GG
Conway
Bruce R
BR
Rybczynski
Philip J
PJ
Demarest
Keith T
KT
D000818:Animals; D002478:Cells, Cultured; D002599:Chalcone / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D047188:Chalcones; D004355:Drug Stability; D006031:Glycosylation; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors; D008862:Microsomes, Liver / Q000378:metabolism; D009004:Monosaccharide Transport Proteins / Q000037:antagonists & inhibitors*; D010695:Phlorhizin / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D011924:Rats, Zucker; D051269:Sodium-Glucose Transporter 1; D051297:Sodium-Glucose Transporter 2; D013329:Structure-Activity Relationship
D047188:Chalcones; D008562:Membrane Glycoproteins; D009004:Monosaccharide Transport Proteins; C495674:SLC5A1 protein, human; C089180:SLC5A2 protein, human; C495676:Slc5a1 protein, rat; D051269:Sodium-Glucose Transporter 1; D051297:Sodium-Glucose Transporter 2; D002599:Chalcone; D010695:Phlorhizin; C015812:dihydrochalcone