Discovery and structure-activity relationships of novel sulfonamides as potent PTP1B inhibitors.
A series of novel sulfonamides containing a single difluoromethylene-phosphonate group were discovered to be potent inhibitors of protein tyrosine phosphatase 1B. Structure-activity relationships around the scaffold were investigated, leading to the identification of compounds with IC50 or Ki values in the low nanomolar range. These sulfonamide-based inhibitors exhibit 100 and 30 times higher inhibitory activity than the corresponding tertiary amines and carboxamides, respectively.
Holmes
Christopher P
CP
Affymax, Inc., 4001 Miranda Avenue, Palo Alto, CA 94304, USA. chris_holmes@affymax.com
Li
Xianfeng
X
Pan
Yijun
Y
Xu
Caiding
C
Bhandari
Ashok
A
Moody
Claire M
CM
Miguel
Joy A
JA
Ferla
Steven W
SW
De Francisco
M Nuria
MN
Frederick
Brian T
BT
Zhou
Siqun
S
Macher
Natalie
N
Jang
Larry
L
Irvine
Jennifer D
JD
Grove
J Russell
JR
D000818:Animals; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D063065:Organophosphonates / Q000138:chemical synthesis / Q000494:pharmacology; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology
D007004:Hypoglycemic Agents; D063065:Organophosphonates; D013449:Sulfonamides; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases