Synthesis and biological activity of selective pipecolic acid-based TNF-alpha converting enzyme (TACE) inhibitors.
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.
Letavic
Michael A
MA
Pfizer Global Research and Development, Groton Laboratories, Eastern Point Road, Groton, CT 06340, USA. michael_a_letavic@groton.pfizer.com
Axt
Matt Z
MZ
Barberia
John T
JT
Carty
Thomas J
TJ
Danley
Dennis E
DE
Geoghegan
Kieran F
KF
Halim
Nadia S
NS
Hoth
Lise R
LR
Kamath
Ajith V
AV
Laird
Ellen R
ER
Lopresti-Morrow
Lori L
LL
McClure
Kim F
KF
Mitchell
Peter G
PG
Natarajan
Vijayalakshmi
V
Noe
Mark C
MC
Pandit
Jayvardhan
J
Reeves
Lisa
L
Schulte
Gayle K
GK
Snow
Sheri L
SL
Sweeney
Francis J
FJ
Tan
Douglas H
DH
Yu
Chul H
CH
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
D004791:Enzyme Inhibitors; D010875:Pipecolic Acids; D013449:Sulfonamides; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human