3-Hydroxy-4-arylsulfonyltetrahydropyranyl-3-hydroxamic acids are novel inhibitors of MMP-13 and aggrecanase.
N-Hydroxy-3-hydroxy-4-arylsulfonyltetrahydropyranyl-3-carboxamides were designed as novel inhibitors of MMP-13 and aggrecanase based on known endocyclic hydroxamate inhibitors of matrix metalloproteinases. These compounds offer favorable physicochemical properties and low metabolic clearance. Synthesis and structure-activity relationships are reported.
Noe
Mark C
MC
Pfizer Global Research and Development, Groton Laboratories, Eastern Point Road, Groton, CT 06340, USA. mark_c_noe@groton.pfizer.com
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
Liras
Jennifer L
JL
Vaughn
Marcie
M
D000818:Animals; D017364:Collagenases / Q000737:chemistry; D010450:Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D020781:Matrix Metalloproteinase 1 / Q000737:chemistry; D053509:Matrix Metalloproteinase 13; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D011714:Pyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D013329:Structure-Activity Relationship
D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D011714:Pyrans; D010450:Endopeptidases; D017364:Collagenases; D053509:Matrix Metalloproteinase 13; C507083:Mmp13 protein, rat; D020781:Matrix Metalloproteinase 1; C083641:aggrecanase