Improving potency and selectivity of a new class of non-Zn-chelating MMP-13 inhibitors.
Discovery and optimization of potency and selectivity of a non-Zn-chelating MMP-13 inhibitor with the aid of protein co-crystal structural information is reported. This inhibitor was observed to have a binding mode distinct from previously published MMP-13 inhibitors. Potency and selectivity were improved by extending the hit structure out from the active site into the S1' pocket.
Heim-Riether
Alexander
A
Boehringer Ingelheim Pharmaceuticals, Department of Medicinal Chemistry, 900 Ridgebury Rd, Ridgefield, CT 06877, USA. alexander.heim-riether@boehringer-ingelheim.com
Taylor
Steven J
SJ
Liang
Shuang
S
Gao
Donghong Amy
DA
Xiong
Zhaoming
Z
Michael August
E
E
Collins
Brandon K
BK
Farmer
Bennett T
BT
Haverty
Kathleen
K
Hill-Drzewi
Melissa
M
Junker
Hans-Dieter
HD
Mariana Margarit
S
S
Moss
Neil
N
Neumann
Thomas
T
Proudfoot
John R
JR
Keenan
Lana Smith
LS
Sekul
Renate
R
Zhang
Qiang
Q
Li
Jun
J
Farrow
Neil A
NA
D020134:Catalytic Domain; D002614:Chelating Agents / Q000737:chemistry / Q000494:pharmacology*; D053509:Matrix Metalloproteinase 13 / Q000737:chemistry / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D013329:Structure-Activity Relationship
D002614:Chelating Agents; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D053509:Matrix Metalloproteinase 13