title: Identification of diarylsulfone sulfonamides as secreted frizzled related protein-1 (sFRP-1) inhibitors.
abstract: 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.
authors.affiliation: Chemical and Screening Sciences, Wyeth Research, 401 N. Middletown Road, Pearl River, New York 10965, USA. gopalsa@wyeth.com
authors.forename: Ariamala
authors.initials: A
authors.lastname: Gopalsamy
authors.forename: Mengxiao
authors.initials: M
authors.lastname: Shi
authors.forename: Barbara
authors.initials: B
authors.lastname: Stauffer
authors.forename: Ramesh
authors.initials: R
authors.lastname: Bahat
authors.forename: Julia
authors.initials: J
authors.lastname: Billiard
authors.forename: Helga
authors.initials: H
authors.lastname: Ponce-de-Leon
authors.forename: Laura
authors.initials: L
authors.lastname: Seestaller-Wehr
authors.forename: Shoichi
authors.initials: S
authors.lastname: Fukayama
authors.forename: Annamarie
authors.initials: A
authors.lastname: Mangine
authors.forename: Robert
authors.initials: R
authors.lastname: Moran
authors.forename: Girija
authors.initials: G
authors.lastname: Krishnamurthy
authors.forename: Peter
authors.initials: P
authors.lastname: Bodine
mesh_terms: 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
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D013449:Sulfonamides; D013450:Sulfones; D000099274:Frizzled-Related Proteins