PTP1B inhibitors: synthesis and evaluation of difluoro-methylenephosphonate bioisosteres on a sulfonamide scaffold.
We have synthesized and evaluated a series of triaryl sulfonamide-based PTP1B inhibitors in which a difluoro-methylenephosphonate group of a potent lead has been replaced by potential bioisosteric replacements. Several mono- or di-charged compounds (8a, 8b, and 15a) were shown exhibit inhibitory activity in the low micromolar range, demonstrating the feasibility of using this approach in identifying non-phosphonate pTyr mimetics in a small molecular scaffold. These results also provide a useful indication of the relative effectiveness of these pTyr mimetics.
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
D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017611:Fluorine Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D009943:Organophosphorus Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry*
D004791:Enzyme Inhibitors; D017611:Fluorine Compounds; D009943:Organophosphorus Compounds; D013449:Sulfonamides; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1