Compelling P1 substituent affect on metalloprotease binding profile enables the design of a novel cyclohexyl core scaffold with excellent MMP selectivity and HER-2 sheddase inhibition.
A serendipitous discovery that the metalloprotease binding profile of a novel class of 2-carboxamide-3-hydroxamic acid piperidines could be significantly attenuated by the modification of the unexplored P1 substituent enabled the design and synthesis of a novel 2-carboxamide-1-hydroxamic acid cyclohexyl scaffold core that exhibited excellent HER-2 potency and unprecedented MMP-selectivity that we believe would not have been possible via conventional P1' perturbations.
Burns
David M
DM
Incyte Corporation, Department of Medicinal Chemistry, Wilmington, DE 19880, USA. dburns@incyte.com
Li
Yun-Long
YL
Shi
Eric
E
He
Chunhong
C
Xu
Meizhong
M
Zhuo
Jincong
J
Zhang
Colin
C
Qian
Ding-Quan
DQ
Li
Yanlong
Y
Wynn
Richard
R
Covington
Maryanne B
MB
Katiyar
Kamna
K
Marando
Cindy A
CA
Fridman
Jordan S
JS
Scherle
Peggy
P
Friedman
Steve
S
Metcalf
Brian
B
Yao
Wenqing
W
D051722:ADAM Proteins / Q000378:metabolism*; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D015195:Drug Design; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D011485:Protein Binding; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D051722:ADAM Proteins; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases; D000970:Antineoplastic Agents; D006877:Hydroxamic Acids; D020778:Matrix Metalloproteinase 2; D008565:Membrane Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; C491236:ADAM10 protein, human