title: Discovery of 3-OH-3-methylpipecolic hydroxamates: potent orally active inhibitors of aggrecanase and MMP-13.
abstract: A series of 3-hydroxy-3-methylpipecolic hydroxamate inhibitors of MMP-13 and aggrecanase was designed based on the observation of increased aggrecanase activity with substitution at the 3-position of the piperidine ring. Potency versus aggrecanase was optimized by modification of the benzyloxyarylsulfonamide group that binds in the S1' pocket. These compounds also possess markedly improved bioavailability and lower metabolic clearance compared to analogous 3,3-dimethyl-5-hydroxypipecolic hydroxamates. These improvements are attributed to lowered lipophilicity proximal to the metabolically labile hydroxamic acid. Synthesis, structure activity relationships, and in vivo efficacy data are described.
authors.affiliation: Pfizer Global Research and Development, Groton Laboratories, Eastern Point Road, Groton 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: Lilli A
authors.initials: LA
authors.lastname: Wolf-Gouveia
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: Ivan
authors.initials: I
authors.lastname: Otterness
authors.forename: Marcia A
authors.initials: MA
authors.lastname: Bliven
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Carty
authors.forename: John T
authors.initials: JT
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
mesh_terms: D000284:Administration, Oral; D000818:Animals; D017364:Collagenases / Q000378:metabolism; D015195:Drug Design; D010450:Endopeptidases / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D053509:Matrix Metalloproteinase 13; D061965:Matrix Metalloproteinase Inhibitors; D015394:Molecular Structure; D010875:Pipecolic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship
chemical_list: D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D010875:Pipecolic Acids; D011480:Protease Inhibitors; D010450:Endopeptidases; D017364:Collagenases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; C083641:aggrecanase