title: Discovery of 3,3-dimethyl-5-hydroxypipecolic hydroxamate-based inhibitors of aggrecanase and MMP-13.
abstract: 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.
authors.affiliation: Pfizer Global Research and Development Groton Laboratories, CT 06340, USA. mark_c_noe@pfizer.com
authors.forename: Mark C
authors.initials: MC
authors.lastname: Noe
authors.forename: Vijayalakshmi
authors.initials: V
authors.lastname: Natarajan
authors.forename: Sheri L
authors.initials: SL
authors.lastname: Snow
authors.forename: Peter G
authors.initials: PG
authors.lastname: Mitchell
authors.forename: Lori
authors.initials: L
authors.lastname: Lopresti-Morrow
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Reeves
authors.forename: Sue A
authors.initials: SA
authors.lastname: Yocum
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Carty
authors.forename: John A
authors.initials: JA
authors.lastname: Barberia
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Sweeney
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Liras
authors.forename: Marcie
authors.initials: M
authors.lastname: Vaughn
authors.forename: Joel R
authors.initials: JR
authors.lastname: Hardink
authors.forename: Joel M
authors.initials: JM
authors.lastname: Hawkins
authors.forename: Christopher
authors.initials: C
authors.lastname: Tokar
mesh_terms: 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*
chemical_list: D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D010450:Endopeptidases; D053509:Matrix Metalloproteinase 13; C083641:aggrecanase