Discovery of gamma-lactam hydroxamic acids as selective inhibitors of tumor necrosis factor alpha converting enzyme: design, synthesis, and structure-activity relationships.
New gamma-lactam TACE inhibitors were designed from known MMP inhibitors. A homology model of TACE was built and examined to identify the S1' site as the key area for TACE selectivity over MMPs. Rational exploration of the P1'-S1' interactions resulted in the discovery of the 3,5-disubstituted benzyl ether as a TACE-selective P1' group. Further optimization led to the discovery of IK682 as a selective and orally bioavailable TACE inhibitor.
Duan
James J-W
JJ
Discovery Chemistry, Bristol-Myers Squibb Company, Experimental Station, Wilmington, Delaware 19880-0500, USA. james.duan@bms.com
Chen
Lihua
L
Wasserman
Zelda R
ZR
Lu
Zhonghui
Z
Liu
Rui-Qin
RQ
Covington
Maryanne B
MB
Qian
Mingxin
M
Hardman
Karl D
KD
Magolda
Ronald L
RL
Newton
Robert C
RC
Christ
David D
DD
Wexler
Ruth R
RR
Decicco
Carl P
CP
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D004285:Dogs; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007769:Lactams / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019278:Matrix Metalloproteinase 3 / Q000737:chemistry; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013552:Swine
D006877:Hydroxamic Acids; C468787:IK 682; D007769:Lactams; D011480:Protease Inhibitors; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3; D000072198:ADAM17 Protein; C000606464:Adam17 protein, rat