Core modification of substituted piperidines as novel inhibitors of HDM2-p53 protein-protein interaction

Bioorg Med Chem Lett. 2014 Apr 15;24(8):1983-6. doi: 10.1016/j.bmcl.2014.02.055.

Weidong Pan ¹, Brian R Lahue ², Yao Ma ², Latha G Nair ¹, Gerald W Shipps Jr ², Yaolin Wang ¹, Ronald Doll ¹, Stéphane L Bogen ³

Affiliations

1 Merck Research Laboratories, Early Development and Discovery Sciences, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
2 Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, United States.
3 Merck Research Laboratories, Early Development and Discovery Sciences, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States. Electronic address: [email protected].

PMID: 24656661 DOI: 10.1016/j.bmcl.2014.02.055

Abstract

The discovery of 3,3-disubstituted piperidine 1 as novel p53-HDM2 inhibitors prompted us to implement subsequent SAR follow up directed towards piperidine core modifications. Conformational restrictions and further functionalization of the piperidine core were investigated as a strategy to gain additional interactions with HDM2. Substitutions at positions 4, 5 and 6 of the piperidine ring were explored. Although some substitutions were tolerated, no significant improvement in potency was observed compared to 1. Incorporation of an allyl side chain at position 2 provided a drastic improvement in binding potency.

Keywords

Cancer; HDM2; Protein–protein interaction; p53.

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