title: 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.
abstract: 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.
authors.affiliation: Incyte Corporation, Department of Medicinal Chemistry, Wilmington, DE 19880, USA. dburns@incyte.com
authors.forename: David M
authors.initials: DM
authors.lastname: Burns
authors.forename: Yun-Long
authors.initials: YL
authors.lastname: Li
authors.forename: Eric
authors.initials: E
authors.lastname: Shi
authors.forename: Chunhong
authors.initials: C
authors.lastname: He
authors.forename: Meizhong
authors.initials: M
authors.lastname: Xu
authors.forename: Jincong
authors.initials: J
authors.lastname: Zhuo
authors.forename: Colin
authors.initials: C
authors.lastname: Zhang
authors.forename: Ding-Quan
authors.initials: DQ
authors.lastname: Qian
authors.forename: Yanlong
authors.initials: Y
authors.lastname: Li
authors.forename: Richard
authors.initials: R
authors.lastname: Wynn
authors.forename: Maryanne B
authors.initials: MB
authors.lastname: Covington
authors.forename: Kamna
authors.initials: K
authors.lastname: Katiyar
authors.forename: Cindy A
authors.initials: CA
authors.lastname: Marando
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Fridman
authors.forename: Peggy
authors.initials: P
authors.lastname: Scherle
authors.forename: Steve
authors.initials: S
authors.lastname: Friedman
authors.forename: Brian
authors.initials: B
authors.lastname: Metcalf
authors.forename: Wenqing
authors.initials: W
authors.lastname: Yao
mesh_terms: 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
chemical_list: 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