Pyran-containing sulfonamide hydroxamic acids: potent MMP inhibitors that spare MMP-1.
The SAR of a series of sterically hindered sulfonamide hydroxamic acids with relatively large P1' groups is described. The compounds typically spare MMP-1 while being potent inhibitors of MMP-13. The metabolically more stable compounds in the series contain either a monocyclic or bicyclic pyran ring adjacent to the hydroxamate group. Despite the sparing of MMP-1, pre-clinical and clinical studies revealed that fibrosis in rats and MSS in humans is still produced.
Reiter
Lawrence A
LA
Pfizer Global Research & Development, Groton Laboratories, Eastern Point Road, Groton, CT 06340, USA. reiterla@groton.pfizer.com
Robinson
Ralph P
RP
McClure
Kim F
KF
Jones
Christopher S
CS
Reese
Matthew R
MR
Mitchell
Peter G
PG
Otterness
Ivan G
IG
Bliven
Marcia L
ML
Liras
Jennifer
J
Cortina
Santo R
SR
Donahue
Kathleen M
KM
Eskra
James D
JD
Griffiths
Richard J
RJ
Lame
Mary E
ME
Lopez-Anaya
Arturo
A
Martinelli
Gary J
GJ
McGahee
Shunda M
SM
Yocum
Sue A
SA
Lopresti-Morrow
Lori L
LL
Tobiassen
Lisa M
LM
Vaughn-Bowser
Marcie L
ML
D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D053509:Matrix Metalloproteinase 13; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D011714:Pyrans / Q000737:chemistry; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry
D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D011714:Pyrans; D013449:Sulfonamides; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; D020782:Matrix Metalloproteinases; D020781:Matrix Metalloproteinase 1