3,4-Disubstituted benzofuran P1' MMP-13 inhibitors: optimization of selectivity and reduction of protein binding.
Potent 3,4-disubstituted benzofuran P1' MMP-13 inhibitors have been prepared. Selectivity over MMP-2 was achieved through a substituent at the C4 position of the benzofuran P1' moiety of the molecule. By replacing a backbone benzene with a pyridine and valine with threonine, compounds (e.g., 44) with greatly reduced plasma protein binding were also obtained.
Li
Wei
W
Department of Chemical Sciences, Wyeth Research, 200 CambridgePark Drive, Cambridge, MA 02140, USA.
Hu
Yonghan
Y
Li
Jianchang
J
Thomason
Jennifer R
JR
DeVincentis
Dianne
D
Du
Xuemei
X
Wu
Junjun
J
Hotchandani
Rajeev
R
Rush
Thomas S
TS
Skotnicki
Jerauld S
JS
Tam
Steve
S
Chockalingam
Priya S
PS
Morris
Elisabeth A
EA
Levin
Jeremy I
JI
D000818:Animals; D001572:Benzofurans / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D011817:Rabbits; D012709:Serum Albumin / Q000737:chemistry; D013329:Structure-Activity Relationship
D001572:Benzofurans; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D012709:Serum Albumin; D053509:Matrix Metalloproteinase 13; D020778:Matrix Metalloproteinase 2