title: Core modification of substituted piperidines as novel inhibitors of HDM2-p53 protein-protein interaction.
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.
authors.affiliation: Merck Research Laboratories, Early Development and Discovery Sciences, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Weidong
authors.initials: W
authors.lastname: Pan
authors.affiliation: Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, United States.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Lahue
authors.affiliation: Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, United States.
authors.forename: Yao
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Merck Research Laboratories, Early Development and Discovery Sciences, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Latha G
authors.initials: LG
authors.lastname: Nair
authors.affiliation: Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, United States.
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Shipps
authors.affiliation: Merck Research Laboratories, Early Development and Discovery Sciences, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Yaolin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Merck Research Laboratories, Early Development and Discovery Sciences, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
authors.forename: Ronald
authors.initials: R
authors.lastname: Doll
authors.affiliation: Merck Research Laboratories, Early Development and Discovery Sciences, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States. Electronic address: Stephane.bogen@merck.com.
authors.forename: Stéphane L
authors.initials: SL
authors.lastname: Bogen
mesh_terms: D001681:Biological Assay; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D010880:Piperidines; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
keywords: Cancer; HDM2; Protein–protein interaction; p53