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

  • ACS Med Chem Lett. 2016 Jan 20;7(3):324-9. doi: 10.1021/acsmedchemlett.5b00472.
Stéphane L Bogen  1 ,  Weidong Pan  1 ,  Craig R Gibeau  2 ,  Brian R Lahue  2 ,  Yao Ma  2 ,  Latha G Nair  1 ,  Elise Seigel  1 ,  Gerald W Shipps Jr  2 ,  Yuan Tian  2 ,  Yaolin Wang  3 ,  Yinghui Lin  3 ,  Ming Liu  3 ,  Suxing Liu  3 ,  Asra Mirza  3 ,  Xiaoying Wang  3 ,  Philip Lipari  3 ,  Cynthia Seidel-Dugan  3 ,  Daniel J Hicklin  3 ,  W Robert Bishop  3 ,  Diane Rindgen  4 ,  Amin Nomeir  4 ,  Winifred Prosise  5 ,  Paul Reichert  5 ,  Giovanna Scapin  5 ,  Corey Strickland  5 ,  Ronald J Doll  1
Affiliations
  • 1. Discovery Chemistry, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
  • 2. Discovery Chemistry, Merck Research Laboratories , Boston, Massachusetts 02115, United States.
  • 3. Discovery Biology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
  • 4. Pharmacokinetic, Pharmacodynamics and Drug Metabolism, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
  • 5. Structural Chemistry, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
PMID: 26985323 DOI: 10.1021/acsmedchemlett.5b00472
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.

Keywords
HDM2; cancer; p53; protein−protein interaction.