Identification of diarylsulfone sulfonamides as secreted frizzled related protein-1 (sFRP-1) inhibitors.
Inhibitor of secreted frizzled related protein-1 (sFRP-1) would be a novel potential osteogenic agent, since loss of sFRP-1 affects osteoblast proliferation, differentiation, and activity, resulting in improved bone mineral density, quality, and strength. We have identified small molecule diarylsulfone sulfonamide derivatives as sFRP-1 inhibitors. Structure-activity relationship generated for various regions of the scaffold was utilized to improve the biochemical profile, resulting in the identification of potent selective analogues, such as 16 with desirable pharmaceutical profile.
Gopalsamy
Ariamala
A
Chemical and Screening Sciences, Wyeth Research, 401 N. Middletown Road, Pearl River, New York 10965, USA. gopalsa@wyeth.com
Shi
Mengxiao
M
Stauffer
Barbara
B
Bahat
Ramesh
R
Billiard
Julia
J
Ponce-de-Leon
Helga
H
Seestaller-Wehr
Laura
L
Fukayama
Shoichi
S
Mangine
Annamarie
A
Moran
Robert
R
Krishnamurthy
Girija
G
Bodine
Peter
P
D000818:Animals; D001671:Biochemistry / Q000379:methods; D015519:Bone Density; D002478:Cells, Cultured; D015195:Drug Design; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008956:Models, Chemical; D010006:Osteoblasts / Q000378:metabolism*; D011506:Proteins / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry*; D013450:Sulfones / Q000737:chemistry*; D000099274:Frizzled-Related Proteins
D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D013449:Sulfonamides; D013450:Sulfones; D000099274:Frizzled-Related Proteins