SAR studies of non-zinc-chelating MMP-13 inhibitors: improving selectivity and metabolic stability.
SAR studies to improve the selectivity and metabolic stability of a class of recently discovered MMP-13 inhibitors are reported. Improved selectivity was achieved by modifying interactions with the S1' pocket. Metabolic stability was improved through reduction of inhibitor lipophilicity. This translated into lower in vivo clearance for the preferred compound.
Gao
Donghong Amy
DA
Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877, USA. amy.gao@boehringer-ingelheim.com
Xiong
Zhaoming
Z
Heim-Riether
Alexander
A
Amodeo
Laura
L
August
E Michael
EM
Cao
Xianhua
X
Ciccarelli
Leonard
L
Collins
Brandon K
BK
Harrington
Kyle
K
Haverty
Kathleen
K
Hill-Drzewi
Melissa
M
Li
Xiang
X
Liang
Shuang
S
Margarit
Steluta Mariana
SM
Moss
Neil
N
Nagaraja
Nelamangala
N
Proudfoot
John
J
Roman
Rene
R
Schlyer
Sabine
S
Keenan
Lana Smith
LS
Taylor
Steven
S
Wellenzohn
Bernd
B
Wiedenmayer
Dieter
D
Li
Jun
J
Farrow
Neil A
NA
D002614:Chelating Agents / Q000737:chemistry / Q000494:pharmacology; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D015032:Zinc / Q000737:chemistry
D002614:Chelating Agents; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D015032:Zinc