Substituted piperidines as HDM2 inhibitors

Yao Ma; Brian R Lahue; Gerald W Shipps Jr; Jeseca Brookes; Yaolin Wang

doi:10.1016/j.bmcl.2014.01.026

Substituted piperidines as HDM2 inhibitors

Bioorg Med Chem Lett. 2014 Feb 15;24(4):1026-30. doi: 10.1016/j.bmcl.2014.01.026. Epub 2014 Jan 17.

Authors

Yao Ma¹, Brian R Lahue², Gerald W Shipps Jr², Jeseca Brookes², Yaolin Wang²

Affiliations

¹ Discovery and Preclinical Sciences, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, United States. Electronic address: yaoma1@yahoo.com.
² Discovery and Preclinical Sciences, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, United States.

PMID: 24486134
DOI: 10.1016/j.bmcl.2014.01.026

Abstract

Novel small molecule HDM2 inhibitor, substituted piperidine, was identified. Initial SAR study indicated potential for several position optimizations. Additional potency enhancement was achieved by introducing a sidechain off the aromatic ring. DMPK study of one of the active compounds has shown a moderate oral PK and reasonable bioavailability.

Keywords: Cancer; HDM2; MDM2; Oncology; Small molecule inhibitor; Substituted piperidine; p53.

MeSH terms

Dose-Response Relationship, Drug
Humans
Molecular Structure
Piperidines / chemical synthesis
Piperidines / chemistry
Piperidines / pharmacology*
Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors*
Structure-Activity Relationship

Substances

Piperidines
MDM2 protein, human
Proto-Oncogene Proteins c-mdm2