Discovery of 3-OH-3-methylpipecolic hydroxamates: potent orally active inhibitors of aggrecanase and MMP-13.
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.
Noe
Mark C
MC
Pfizer Global Research and Development, Groton Laboratories, Eastern Point Road, Groton CT 06340, USA. mark.c.noe@pfizer.com
Natarajan
Vijayalakshmi
V
Snow
Sheri L
SL
Wolf-Gouveia
Lilli A
LA
Mitchell
Peter G
PG
Lopresti-Morrow
Lori
L
Reeves
Lisa M
LM
Yocum
Sue A
SA
Otterness
Ivan
I
Bliven
Marcia A
MA
Carty
Thomas J
TJ
Barberia
John T
JT
Sweeney
Francis J
FJ
Liras
Jennifer L
JL
Vaughn
Marcie
M
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
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