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

David M Burns; Yun-Long Li; Eric Shi; Chunhong He; Meizhong Xu; Jincong Zhuo; Colin Zhang; Ding-Quan Qian; Yanlong Li; Richard Wynn; Maryanne B Covington; Kamna Katiyar; Cindy A Marando; Jordan S Fridman; Peggy Scherle; Steve Friedman; Brian Metcalf; Wenqing Yao

doi:10.1016/j.bmcl.2009.04.143

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

Bioorg Med Chem Lett. 2009 Jul 1;19(13):3525-30. doi: 10.1016/j.bmcl.2009.04.143. Epub 2009 May 5.

Authors

David M Burns¹, Yun-Long Li, Eric Shi, Chunhong He, Meizhong Xu, Jincong Zhuo, Colin Zhang, Ding-Quan Qian, Yanlong Li, Richard Wynn, Maryanne B Covington, Kamna Katiyar, Cindy A Marando, Jordan S Fridman, Peggy Scherle, Steve Friedman, Brian Metcalf, Wenqing Yao

Affiliation

¹ Incyte Corporation, Department of Medicinal Chemistry, Wilmington, DE 19880, USA. dburns@incyte.com

PMID: 19457660
DOI: 10.1016/j.bmcl.2009.04.143

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.

MeSH terms

ADAM Proteins / metabolism*
ADAM10 Protein
Amyloid Precursor Protein Secretases / metabolism*
Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Cell Line, Tumor
Drug Design
Humans
Hydroxamic Acids / chemical synthesis*
Hydroxamic Acids / chemistry
Hydroxamic Acids / pharmacology
Matrix Metalloproteinase 2 / metabolism
Membrane Proteins / metabolism*
Protein Binding
Receptor, ErbB-2 / metabolism*
Structure-Activity Relationship
Substrate Specificity

Substances

Antineoplastic Agents
Hydroxamic Acids
Membrane Proteins
Receptor, ErbB-2
Amyloid Precursor Protein Secretases
ADAM Proteins
Matrix Metalloproteinase 2
ADAM10 Protein
ADAM10 protein, human