Conversion of potent MMP inhibitors into selective TACE inhibitors.
Novel sultam hydroxamates with potent MMP activity were transformed into potent TACE inhibitors, lacking MMP activity. To accomplish this we relied on structural differences between the MMP and TACE S1' pockets and the known advantageous fit of a 2-methyl-4-quinolinylmethoxyphenyl group into this region. From this approach, compound 7d was identified as a potent TACE inhibitor (IC50 = 3.7 nM) that lacked MMP-1, -2, -9, and -13 activity.
Cherney
Robert J
RJ
Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA. robert.cherney@bms.com
King
Bryan W
BW
Gilmore
John L
JL
Liu
Rui-Qin
RQ
Covington
Maryanne B
MB
Duan
James J-W
JJ
Decicco
Carl P
CP
D051722:ADAM Proteins / Q000037:antagonists & inhibitors*; D000072198:ADAM17 Protein; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045726:Metalloproteases / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D013449:Sulfonamides; D045726:Metalloproteases; D051722:ADAM Proteins; D000072198:ADAM17 Protein