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.
Incyte Corporation, Department of Medicinal Chemistry, Wilmington, DE 19880, USA. wyao@incyte.com
Wenqing
W
Yao
Jincong
J
Zhuo
David M
DM
Burns
Yun-Long
YL
Li
Ding-Quan
DQ
Qian
Colin
C
Zhang
Chunhong
C
He
Meizhong
M
Xu
Eric
E
Shi
Yanlong
Y
Li
Cindy A
CA
Marando
Maryanne B
MB
Covington
Gengjie
G
Yang
Xiangdong
X
Liu
Max
M
Pan
Jordan S
JS
Fridman
Peggy
P
Scherle
Zelda R
ZR
Wasserman
Gregory
G
Hollis
Kris
K
Vaddi
Swamy
S
Yeleswaram
Robert
R
Newton
Steve
S
Friedman
Brian
B
Metcalf
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