Design and identification of selective HER-2 sheddase inhibitors via P1' manipulation and unconventional P2' perturbations to induce a molecular metamorphosis.
In an effort to obtain a MMP selective and potent inhibitor of HER-2 sheddase (ADAM-10), the P1' group of a novel class of (6S,7S)-7-[(hydroxyamino)carbonyl]-6-carboxamide-5-azaspiro[2.5]octane-5-carboxylates was attenuated and the structure-activity relationships (SAR) will be discussed. In addition, it was discovered that unconventional perturbation of the P2' moiety could confer MMP selectivity, which was hypothesized to be a manifestation of the P2' group effecting global conformational changes.
Yao
Wenqing
W
Incyte Corporation, Department of Medicinal Chemistry, Wilmington, DE 19880, USA. wyao@incyte.com
Zhuo
Jincong
J
Burns
David M
DM
Li
Yun-Long
YL
Qian
Ding-Quan
DQ
Zhang
Colin
C
He
Chunhong
C
Xu
Meizhong
M
Shi
Eric
E
Li
Yanlong
Y
Marando
Cindy A
CA
Covington
Maryanne B
MB
Yang
Gengjie
G
Liu
Xiangdong
X
Pan
Max
M
Fridman
Jordan S
JS
Scherle
Peggy
P
Wasserman
Zelda R
ZR
Hollis
Gregory
G
Vaddi
Kris
K
Yeleswaram
Swamy
S
Newton
Robert
R
Friedman
Steve
S
Metcalf
Brian
B
D051722:ADAM Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000072197:ADAM10 Protein; D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001372:Aza Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D051722:ADAM Proteins; D000072197:ADAM10 Protein; D000577:Amides; D053829:Amyloid Precursor Protein Secretases; D001372:Aza Compounds; D006877:Hydroxamic Acids; D008565:Membrane Proteins; D047428:Protein Kinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; D013141:Spiro Compounds; C491236:ADAM10 protein, human