Discovery and characterization of the potent, selective and orally bioavailable MMP inhibitor ABT-770.
Modification of the biphenyl portion of MMP inhibitor 2a gave analogue 2i which is greater than 1000-fold selective against MMP-2 versus MMP-1. The stereospecific synthesis of both enantiomers of 2i was achieved beginning with (S)- or (R)-benzyl glycidyl ether. The (S)-enantiomer, 11 (ABT-770), is orally bioavailable and efficacious in an in vivo model of tumor growth.
Curtin
M L
ML
Cancer Research Area, Abbott Laboratories, Dept. 47J, Bldg. AP10, 100 Abbott Park Road, Abbott Park, IL 60064, USA. mike.curtin@abbott.com
Florjancic
A S
AS
Heyman
H R
HR
Michaelides
M R
MR
Garland
R B
RB
Holms
J H
JH
Steinman
D H
DH
Dellaria
J F
JF
Gong
J
J
Wada
C K
CK
Guo
Y
Y
Elmore
I B
IB
Tapang
P
P
Albert
D H
DH
Magoc
T J
TJ
Marcotte
P A
PA
Bouska
J J
JJ
Goodfellow
C L
CL
Bauch
J L
JL
Marsh
K C
KC
Morgan
D W
DW
Davidsen
S K
SK
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics; D019540:Area Under Curve; D001682:Biological Availability; D001713:Biphenyl Compounds / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D002455:Cell Division / Q000187:drug effects; D004285:Dogs; D004791:Enzyme Inhibitors / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics; D006207:Half-Life; D000882:Haplorhini; D006877:Hydroxamic Acids / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D020128:Inhibitory Concentration 50; D007275:Injections, Intravenous; D061965:Matrix Metalloproteinase Inhibitors; D008657:Metabolic Clearance Rate; D009374:Neoplasms, Experimental / Q000188:drug therapy; D051381:Rats; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; C442959:ABT-770