Modulation of Wnt signaling through inhibition of secreted frizzled-related protein I (sFRP-1) with N-substituted piperidinyl diphenylsulfonyl sulfonamides.
The diphenylsulfonyl sulfonamide scaffold represented by 1 (WAY-316606) are small molecule inhibitors of the secreted protein sFRP-1, an endogenous antagonist of the secreted glycoprotein Wnt. Modulators of the Wnt pathway have been proposed as anabolic agents for the treatment of osteoporosis or other bone-related disorders. Details of the structure-activity relationships and biological activity from the first structural class of this scaffold will be discussed.
Moore
William J
WJ
Chemical and Screening Sciences, Wyeth Research, Collegeville, Pennsylvania 19426, USA. moorew2@wyeth.com
Kern
Jeffrey C
JC
Bhat
Ramesh
R
Commons
Thomas J
TJ
Fukayama
Shoichi
S
Goljer
Igor
I
Krishnamurthy
Girija
G
Magolda
Ronald L
RL
Nogle
Lisa
L
Pitts
Keith
K
Stauffer
Barb
B
Trybulski
Eugene J
EJ
Welmaker
Gregory S
GS
Wilson
Matthew
M
Bodine
Peter V N
PV
D000818:Animals; D045744:Cell Line, Tumor; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D020128:Inhibitory Concentration 50; D047908:Intracellular Signaling Peptides and Proteins; D007536:Isomerism; D051379:Mice; D015394:Molecular Structure; D010880:Piperidines / Q000737:chemistry*; D011485:Protein Binding; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D012886:Skull / Q000187:drug effects; D013329:Structure-Activity Relationship; D013424:Sulfanilamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D000099274:Frizzled-Related Proteins
D047908:Intracellular Signaling Peptides and Proteins; D010880:Piperidines; D011506:Proteins; D013424:Sulfanilamides; D051153:Wnt Proteins; D000099274:Frizzled-Related Proteins; C032727:piperidine