Structure-activity relationship study of 4-substituted piperidines at Leu26 moiety of novel p53-hDM2 inhibitors

Yuan Tian; Yao Ma; Craig R Gibeau; Brian R Lahue; Gerald W Shipps Jr; Corey Strickland; Stéphane L Bogen

doi:10.1016/j.bmcl.2016.03.078

Structure-activity relationship study of 4-substituted piperidines at Leu26 moiety of novel p53-hDM2 inhibitors

Bioorg Med Chem Lett. 2016 Jun 1;26(11):2735-8. doi: 10.1016/j.bmcl.2016.03.078. Epub 2016 Mar 23.

Authors

Yuan Tian¹, Yao Ma², Craig R Gibeau², Brian R Lahue², Gerald W Shipps Jr², Corey Strickland³, Stéphane L Bogen³

Affiliations

¹ Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA. Electronic address: yuan.tian2@merck.com.
² Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
³ Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.

PMID: 27080185
DOI: 10.1016/j.bmcl.2016.03.078

Abstract

Led by the structural information of the screening hit with mDM2 protein, a structure modification of Leu26 moiety of the novel p53-hDM2 inhibitors was conducted. A structure-activity relationship study of 4-substituted piperidines revealed compound 20t with good potencies and excellent CYP450 profiles.

Keywords: SAR; hDM2; p53.

MeSH terms

Dose-Response Relationship, Drug
Humans
Leucine / chemistry*
Models, Molecular
Molecular Structure
Piperidines / chemical synthesis
Piperidines / chemistry
Piperidines / pharmacology*
Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors*
Proto-Oncogene Proteins c-mdm2 / metabolism
Structure-Activity Relationship
Tumor Suppressor Protein p53 / antagonists & inhibitors*
Tumor Suppressor Protein p53 / metabolism

Substances

Piperidines
Tumor Suppressor Protein p53
MDM2 protein, human
Proto-Oncogene Proteins c-mdm2
Leucine