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

Autor: Bogen SL; Discovery Chemistry, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States., Pan W; Discovery Chemistry, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States., Gibeau CR; Discovery Chemistry, Merck Research Laboratories , Boston, Massachusetts 02115, United States., Lahue BR; Discovery Chemistry, Merck Research Laboratories , Boston, Massachusetts 02115, United States., Ma Y; Discovery Chemistry, Merck Research Laboratories , Boston, Massachusetts 02115, United States., Nair LG; Discovery Chemistry, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States., Seigel E; Discovery Chemistry, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States., Shipps GW Jr; Discovery Chemistry, Merck Research Laboratories , Boston, Massachusetts 02115, United States., Tian Y; Discovery Chemistry, Merck Research Laboratories , Boston, Massachusetts 02115, United States., Wang Y; Discovery Biology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States., Lin Y; Discovery Biology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States., Liu M; Discovery Biology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States., Liu S; Discovery Biology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States., Mirza A; Discovery Biology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States., Wang X; Discovery Biology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States., Lipari P; Discovery Biology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States., Seidel-Dugan C; Discovery Biology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States., Hicklin DJ; Discovery Biology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States., Bishop WR; Discovery Biology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States., Rindgen D; Pharmacokinetic, Pharmacodynamics and Drug Metabolism, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States., Nomeir A; Pharmacokinetic, Pharmacodynamics and Drug Metabolism, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States., Prosise W; Structural Chemistry, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States., Reichert P; Structural Chemistry, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States., Scapin G; Structural Chemistry, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States., Strickland C; Structural Chemistry, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States., Doll RJ; Discovery Chemistry, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
Jazyk: angličtina
Zdroj: ACS medicinal chemistry letters [ACS Med Chem Lett] 2016 Jan 20; Vol. 7 (3), pp. 324-9. Date of Electronic Publication: 2016 Jan 20 (Print Publication: 2016).
DOI: 10.1021/acsmedchemlett.5b00472
Abstrakt: 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.
Databáze: MEDLINE
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