title: Continued exploration of biphenylsulfonamide scaffold as a platform for aggrecanase-1 inhibition.
abstract: Design, synthesis and structure-activity relationship of a series of biphenylsulfonamido-3-methylbutanoic acid based aggrecanase-1 inhibitors are described. In addition to robust aggrecanase-1 inhibition, these compounds also exhibit potent MMP-13 activity. In cell-based cartilage explants assay compound 48 produced 87% inhibition of proteoglycan degradation at 10 μg/mL. Good pharmacokinetic properties were demonstrated by 46 with a half-life of 6h and bioavailability of 23%.
authors: Worldwide Medicinal Chemistry, Pfizer Global Research and Development, 200 CambridgePark Drive, Cambridge, MA 02140, USA.
authors: Yonghan
authors: Y
authors: Hu
authors: Li
authors: L
authors: Xing
authors: Jennifer R
authors: JR
authors: Thomason
authors: Jason
authors: J
authors: Xiang
authors: Manus
authors: M
authors: Ipek
authors: Satenig
authors: S
authors: Guler
authors: Huanqiu
authors: H
authors: Li
authors: Joshua
authors: J
authors: Sabatini
authors: Priya
authors: P
authors: Chockalingam
authors: Erica
authors: E
authors: Reifenberg
authors: Richard
authors: R
authors: Sheldon
authors: Elisabeth A
authors: EA
authors: Morris
authors: Katy E
authors: KE
authors: Georgiadis
authors: Steve
authors: S
authors: Tam
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000071121:ADAMTS4 Protein; D000818:Animals; D001713:Biphenyl Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D008958:Models, Molecular; D010003:Osteoarthritis / Q000188:drug therapy; D011348:Procollagen N-Endopeptidase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011480:Protease Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011509:Proteoglycans / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D001713:Biphenyl Compounds; D011480:Protease Inhibitors; D011509:Proteoglycans; D013449:Sulfonamides; D051722:ADAM Proteins; D053509:Matrix Metalloproteinase 13; D011348:Procollagen N-Endopeptidase; D000071121:ADAMTS4 Protein