Evaluation of the inhibition of other metalloproteinases by matrix metalloproteinase inhibitors.
Two series of compounds synthesized as specific matrix metalloproteinase (MMP) inhibitors have been evaluated for their inhibition of non-MMPs. In a series of substituted succinyl hydroxamic acids, some were found to be significant (IC50 < 1 microM) inhibitors of leucine (microsomal) aminopeptidase, neprilysin (3.4.24.11), and thermolysin. Macrocyclic compounds in which the alpha carbon of the succinyl hydroxamate is linked to the side chain of the P2' amino acid were found to be good inhibitors of aminopeptidase, but not of neprilysin or thermolysin. Compounds of neither series were found to be significant inhibitors of angiotensin converting enzyme or carboxypeptidase A.
Marcotte
P A
PA
Cancer Research, Pharmaceutical Discovery Division, Abbott Laboratories, Abbott Park, IL 60064, USA. pat.a.marcotte@abbott.com
Elmore
I N
IN
Guan
Z
Z
Magoc
T J
TJ
Albert
D H
DH
Morgand
D W
DW
Curtin
M L
ML
Garland
R B
RB
Guo
Y
Y
Heyman
H R
HR
Holms
J H
JH
Sheppard
G S
GS
Steinman
D H
DH
Wada
C K
CK
Davidsen
S K
SK
D000806:Angiotensin-Converting Enzyme Inhibitors; D000818:Animals; D001426:Bacterial Proteins; D002268:Carboxypeptidases / Q000037:antagonists & inhibitors; D043422:Carboxypeptidases A; D002417:Cattle; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000378:metabolism; D020128:Inhibitory Concentration 50; D007931:Leucyl Aminopeptidase / Q000037:antagonists & inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D015260:Neprilysin / Q000037:antagonists & inhibitors; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D013552:Swine; D013820:Thermolysin / Q000037:antagonists & inhibitors; D015032:Zinc / Q000378:metabolism
D000806:Angiotensin-Converting Enzyme Inhibitors; D001426:Bacterial Proteins; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D002268:Carboxypeptidases; D007931:Leucyl Aminopeptidase; D043422:Carboxypeptidases A; D008666:Metalloendopeptidases; D015260:Neprilysin; D013820:Thermolysin; D015032:Zinc