title: Synthesis and biological activity of selective pipecolic acid-based TNF-alpha converting enzyme (TACE) inhibitors.
abstract: A series of novel, selective TNF-alpha converting enzyme inhibitors based on 4-hydroxy and 5-hydroxy pipecolate hydroxamic acid scaffolds is described. The potency and selectivity of TACE inhibition is dramatically influenced by the nature of the sulfonamide group which interacts with the S1' site of the enzyme. Substituted 4-benzyloxybenzenesulfonamides exhibit excellent TACE potency with >100x selectivity over inhibition of matrix metalloprotease-1 (MMP-1). Alkyl substituents on the ortho position of the benzyl ether moiety give the most potent inhibition of TNF-alpha release in LPS-treated human whole blood.
authors: Pfizer Global Research and Development, Groton Laboratories, Eastern Point Road, Groton, CT 06340, USA. michael_a_letavic@groton.pfizer.com
authors: Michael A
authors: MA
authors: Letavic
authors: Matt Z
authors: MZ
authors: Axt
authors: John T
authors: JT
authors: Barberia
authors: Thomas J
authors: TJ
authors: Carty
authors: Dennis E
authors: DE
authors: Danley
authors: Kieran F
authors: KF
authors: Geoghegan
authors: Nadia S
authors: NS
authors: Halim
authors: Lise R
authors: LR
authors: Hoth
authors: Ajith V
authors: AV
authors: Kamath
authors: Ellen R
authors: ER
authors: Laird
authors: Lori L
authors: LL
authors: Lopresti-Morrow
authors: Kim F
authors: KF
authors: McClure
authors: Peter G
authors: PG
authors: Mitchell
authors: Vijayalakshmi
authors: V
authors: Natarajan
authors: Mark C
authors: MC
authors: Noe
authors: Jayvardhan
authors: J
authors: Pandit
authors: Lisa
authors: L
authors: Reeves
authors: Gayle K
authors: GK
authors: Schulte
authors: Sheri L
authors: SL
authors: Snow
authors: Francis J
authors: FJ
authors: Sweeney
authors: Douglas H
authors: DH
authors: Tan
authors: Chul H
authors: CH
authors: Yu
mesh_terms: D051722:ADAM Proteins; D000072198:ADAM17 Protein; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D008968:Molecular Conformation; D010875:Pipecolic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D010875:Pipecolic Acids; D013449:Sulfonamides; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human