Discovery of Novel 3,3-Disubstituted Piperidines as Orally Bioavailable, Potent, and Efficacious HDM2-p53 Inhibitors.
Basic Information
ID: ALA3804796
Journal: ACS Med Chem Lett
Title: Discovery of Novel 3,3-Disubstituted Piperidines as Orally Bioavailable, Potent, and Efficacious HDM2-p53 Inhibitors.
Authors: Bogen SL, Pan W, Gibeau CR, Lahue BR, Ma Y, Nair LG, Seigel E, Shipps GW, Tian Y, Wang Y, Lin Y, Liu M, Liu S, Mirza A, Wang X, Lipari P, Seidel-Dugan C, Hicklin DJ, Bishop WR, Rindgen D, Nomeir A, Prosise W, Reichert P, Scapin G, Strickland C, Doll RJ.
Abstract: 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.
CiteXplore: 26985323
DOI: 10.1021/acsmedchemlett.5b00472
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