Substituted piperidines as HDM2 inhibitors

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

doi:10.1016/j.bmcl.2014.01.026

Cited by 16 publications

(18 citation statements)

References 24 publications

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“…The substituted piperidines 14a and 14b were identified as hits with micromolar potency by a screening campaign at Merck using a MDM2-p53 fluorescence polarization assay (Figure 7) [32]. Optimization of the piperazine amide moiety showed that replacement of the pyridine nitrogen with an alkoxy substituent gave improved potency, and the 2-methoxyethoxy substituent was taken into the next round of SAR (14c, Table 6).…”

Section: Rg7388 Seriesmentioning

confidence: 99%

Small-Molecule MDM2-p53 Inhibitors: Recent Advances

2015

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Potent and selective small-molecule inhibitors of the p53-MDM2 interaction intended for the treatment of p53 wild-type tumors have been designed and optimized in a number of chemical series. This review details recent disclosures of compounds in advanced optimization and features key series that have given rise to clinical trial candidates. The structure-activity relationships for inhibitor classes are discussed with reference to x-ray structures, and common structural features are identified.

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Section: Rg7388 Seriesmentioning

confidence: 99%

Small-Molecule MDM2-p53 Inhibitors: Recent Advances

2015

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“…Merck scientists have reported a class of piperidine-containing compounds as MDM2 inhibitors with IC 50 values as low as 41 nM [73]. Novartis has explored several small molecular scaffolds such as 3-imidazolylindoles, substituted dihydroimidazole derivatives, tetrasubstituted heteroaryl compounds, and substituted isoquinolinones and quinazolinones as inhibitors of MDM2 and/or MDMX [74].…”

Section: Small Molecules As Inhibitors Of Mdm2-p5interactionmentioning

confidence: 99%

Spiro-oxindoles as a Promising Class of Small Molecule Inhibitors of p53–MDM2 Interaction Useful in Targeted Cancer Therapy

et al. 2016

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As a result of the toxicity of currently available anticancer drugs and the inefficiency of chemotherapeutic treatments, the design and discovery of effective and selective antitumor agents continues to be a hot topic in organic medicinal chemistry. Targeted therapy is a newer type of cancer treatment that uses drugs designed to interfere with specific molecules necessary for tumor growth and progression. This review explains the mechanism of regulation of p53 (tumor suppressor protein) by MDM2 and illustrates the role of targeting p53-MDM2 protein-protein interaction using small molecules as a new cancer therapeutic strategy. Spirocyclic oxindoles or spiro-oxindoles, with a rigid heterocyclic ring fused at the 3-position of the oxindole core with varied substitution around it, are the most efficacious class of small molecules which inhibit cell proliferation and induce apoptosis in cancer cells, leading to complete tumor growth regression without affecting activities of normal cells. In this review, we present a comprehensive account of the systematic development of and recent progress in diverse spiro-oxindole derivatives active as potent selective inhibitors of p53-MDM2 interaction with special emphasis on spiro-pyrrolidinyl oxindoles (the MI series), their mechanism of action, and structure-activity relationship. This review will help in understanding the molecular mechanism of p53 reactivation by spiro-oxindoles in tumor tissues and also facilitates the design and exploration of more potent analogues with high efficacy and low side effects for the treatment of cancer. Recent progress in spiro-oxindole derivatives as potent small molecule inhibitors of p53-MDM2 interaction, useful as anticancer agents, is described with reference to their mechanism of action and structure-activity relationship.

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“…As described earlier, 20,23,24 the team capitalized on the Bargellini reaction of protected 3-piperidinone 26a and 26b with various alcohol moieties to assemble in one-pot the gemdisubstituted piperidine core of type 27a and 27b. 20 Efficient acid chloride coupling procedures were developed to install 4-(trifluoromethyl)-nicotinic acid 28 as well as 1-(2-alkoxyphenyl)piperazine hydrochloride of type 32 into final targets. Another synthetic approach relied on standard HATU coupling procedures, installing first 1-(2-alkoxyphenyl)-piperazine moieties 32 then 4-(trifluoromethyl)-nicotinic acid 28 to deliver compounds of type 34.…”

Section: * S Supporting Informationmentioning

confidence: 99%

Discovery of Novel 3,3-Disubstituted Piperidines as Orally Bioavailable, Potent, and Efficacious HDM2-p53 Inhibitors

Bogen

Pan

Gibeau

et al. 2016

ACS Med. Chem. Lett.

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A new subseries of substituted piperidines as p53-HDM2 inhibitors exemplified by 21 has been developed from the initial lead 1. Research focused on optimization of a crucial HDM2 Trp23−ligand interaction led to the identification of 2-(trifluoromethyl)thiophene as the preferred moiety. Further investigation of the Leu26 pocket resulted in potent, novel substituted piperidine inhibitors of the HDM2-p53 interaction that demonstrated tumor regression in several human cancer xenograft models in mice. The structure of HDM2 in complex with inhibitors 3, 10, and 21 is described.

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Substituted piperidines as HDM2 inhibitors

Cited by 16 publications

References 24 publications

Small-Molecule MDM2-p53 Inhibitors: Recent Advances

Small-Molecule MDM2-p53 Inhibitors: Recent Advances

Spiro-oxindoles as a Promising Class of Small Molecule Inhibitors of p53–MDM2 Interaction Useful in Targeted Cancer Therapy

Discovery of Novel 3,3-Disubstituted Piperidines as Orally Bioavailable, Potent, and Efficacious HDM2-p53 Inhibitors

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