Identification of potent and selective TACE inhibitors via the S1 pocket.
By focusing on the P1 portion of the piperidine beta-sulfone ligands we identified a motif that induces selectivity and resulted in a series of TACE inhibitors that demonstrated excellent in vitro potency against isolated TACE enzyme and excellent selectivity over MMPs 1, 2, 9, 13, and 14.
Condon
Jeffrey S
JS
Chemical and Screening Sciences, Wyeth Research, 200 Cambridge Park Drive, Cambridge, MA 02140, USA.
Joseph-McCarthy
Diane
D
Levin
Jeremy I
JI
Lombart
Henry-Georges
HG
Lovering
Frank E
FE
Sun
Linhong
L
Wang
Weiheng
W
Xu
Weixin
W
Zhang
Yuhua
Y
D051722:ADAM Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D000072198:ADAM17 Protein; D018360:Crystallography, X-Ray; D008024:Ligands; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors; D010880:Piperidines / Q000737:chemistry; D011480:Protease Inhibitors / Q000737:chemistry* / Q000302:isolation & purification* / Q000494:pharmacology; D013450:Sulfones / Q000737:chemistry
D008024:Ligands; D010880:Piperidines; D011480:Protease Inhibitors; D013450:Sulfones; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein