Conversion of an MMP-potent scaffold to an MMP-selective HER-2 sheddase inhibitor via scaffold hybridization and subtle P1' permutations.
A series of beta-sulfonamide piperidine hydroxamates were prepared and shown to be potent inhibitors of the human epidermal growth factor receptor-2 (HER-2) sheddase with excellent selectivity against MMP-1, -2, -3, and -9. This was achieved by exploiting subtle differences within the otherwise highly conserved S(1)(') binding pocket of the active sites within the metalloprotease family. In addition, it was discovered that the introduction of polarity to the P(1) and P(1)(') groups reduced the projected human clearance.
Burns
David M
DM
Department of Medicinal Chemistry, Incyte Corporation, Wilmington, DE 19880, USA. dburns@incyte.com
He
Chunhong
C
Li
Yanlong
Y
Scherle
Peggy
P
Liu
Xiangdong
X
Marando
Cindy A
CA
Covington
Mayanne B
MB
Yang
Gengjie
G
Pan
Max
M
Turner
Sharon
S
Fridman
Jordan S
JS
Hollis
Gregory
G
Vaddi
Kris
K
Yeleswaram
Swamy
S
Newton
Robert
R
Friedman
Steve
S
Metcalf
Brian
B
Yao
Wenqing
W
D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D020782:Matrix Metalloproteinases / Q000737:chemistry / Q000378:metabolism*; D010880:Piperidines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry
D004791:Enzyme Inhibitors; D020782:Matrix Metalloproteinases; D010880:Piperidines; D018719:Erb-b2 Receptor Tyrosine Kinases