Development of new hydroxamate matrix metalloproteinase inhibitors derived from functionalized 4-aminoprolines.
A series of hydroxamates was prepared from an aminoproline scaffold and tested for efficacy as matrix metalloproteinase (MMP) inhibitors. Detailed SAR for the series is reported for five enzymes within the MMP family, and a number of inhibitors, such as compound 47, display broad-spectrum activity with sub-nanomolar potency for some enzymes. Modifications of the P1' portion of the molecule played a key role in affecting both potency and selectivity within the MMP family. Longer-chain aliphatic substituents in this region of the molecule tended to increase potency for MMP-3 and decrease potency for MMP-1, as exemplified by compounds 48-50, while aromatic substituents, as in compound 52, generated broad-spectrum inhibition. The data is rationalized based upon X-ray crystal data which is also presented. While the in vitro peroral absorption seemed to be less predictable, it tended to decrease with longer and more hydrophilic substituents. Finally, a rat model of osteoarthritis was used to evaluate the efficacy of these compounds, and a direct link was established between their pharmacokinetics and their in vivo efficacy.
Natchus
M G
MG
Procter and Gamble Pharmaceuticals, 8700 Mason-Montgomery Road, Mason, Ohio 45040, USA. natchus.mg@pg.com
Bookland
R G
RG
De
B
B
Almstead
N G
NG
Pikul
S
S
Janusz
M J
MJ
Heitmeyer
S A
SA
Hookfin
E B
EB
Hsieh
L C
LC
Dowty
M E
ME
Dietsch
C R
CR
Patel
V S
VS
Garver
S M
SM
Gu
F
F
Pokross
M E
ME
Mieling
G E
GE
Baker
T R
TR
Foltz
D J
DJ
Peng
S X
SX
Bornes
D M
DM
Strojnowski
M J
MJ
Taiwo
Y O
YO
D000818:Animals; D002358:Cartilage, Articular / Q000473:pathology; D018360:Crystallography, X-Ray; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007461:Iodoacetates; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000737:chemistry; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D020370:Osteoarthritis, Knee / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D011392:Proline / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D006877:Hydroxamic Acids; D007461:Iodoacetates; D011480:Protease Inhibitors; D011392:Proline; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3