The design, synthesis, and structure-activity relationships of a series of macrocyclic MMP inhibitors.
A series of succinate-derived hydroxamic acids incorporating a macrocyclic ring were designed, synthesized, and evaluated as inhibitors of matrix metalloproteinases. The inhibitors were designed based on the published X-ray crystal structure of batimastat (1) complexed with human neutrophil collagenase (MMP-8). The synthesized compounds were shown to inhibit selected MMPs in vitro with low nanomolar potency.
Steinman
D H
DH
Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, IL 60064, USA.
Curtin
M L
ML
Garland
R B
RB
Davidsen
S K
SK
Heyman
H R
HR
Holms
J H
JH
Albert
D H
DH
Magoc
T J
TJ
Nagy
I B
IB
Marcotte
P A
PA
Li
J
J
Morgan
D W
DW
Hutchins
C
C
Summers
J B
JB
D017364:Collagenases / Q000737:chemistry*; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007202:Indicators and Reagents; D007700:Kinetics; D020784:Matrix Metalloproteinase 8; D061965:Matrix Metalloproteinase Inhibitors; D008958:Models, Molecular; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013386:Succinates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology
D006877:Hydroxamic Acids; D007202:Indicators and Reagents; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D013386:Succinates; D013876:Thiophenes; D010649:Phenylalanine; C080985:batimastat; D017364:Collagenases; D020784:Matrix Metalloproteinase 8