Discovery of 3,3-dimethyl-5-hydroxypipecolic hydroxamate-based inhibitors of aggrecanase and MMP-13.
A series of pipecolic hydroxamate inhibitors of MMP-13 and aggrecanase was discovered based on screening known inhibitors of TNF-alpha converting enzyme (TACE). Potency versus aggrecanase was optimized by modification of the benzyloxyarylsulfonamide group. Incorporation of geminal alkyl substitution at the 3-position of the piperidine ring improved metabolic stability, presumably by increasing steric hindrance around the metabolically labile hydroxamic acid. This modification also resulted in dramatic improvement of aggrecanase activity with a slight reduction in selectivity versus MMP-1. Synthesis, structure activity relationships, and strategies to reduce metabolic clearance are described.
Noe
Mark C
MC
Pfizer Global Research and Development Groton Laboratories, CT 06340, USA. mark_c_noe@pfizer.com
Natarajan
Vijayalakshmi
V
Snow
Sheri L
SL
Mitchell
Peter G
PG
Lopresti-Morrow
Lori
L
Reeves
Lisa M
LM
Yocum
Sue A
SA
Carty
Thomas J
TJ
Barberia
John A
JA
Sweeney
Francis J
FJ
Liras
Jennifer L
JL
Vaughn
Marcie
M
Hardink
Joel R
JR
Hawkins
Joel M
JM
Tokar
Christopher
C
D010450:Endopeptidases / Q000187:drug effects*; D006877:Hydroxamic Acids / Q000737:chemistry / Q000494:pharmacology*; D053509:Matrix Metalloproteinase 13; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*
D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D010450:Endopeptidases; D053509:Matrix Metalloproteinase 13; C083641:aggrecanase