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Bogen SL, Pan W, Gibeau CR, et al. Discovery of Novel 3,3-Disubstituted Piperidines as Orally Bioavailable, Potent, and Efficacious HDM2-p53 Inhibitors. ACS Med Chem Lett. 2016;7(3):324-9doi: 10.1021/acsmedchemlett.5b00472.
Bogen, S. L., Pan, W., Gibeau, C. R., Lahue, B. R., Ma, Y., Nair, L. G., Seigel, E., Shipps, G. W., Tian, Y., Wang, Y., Lin, Y., Liu, M., Liu, S., Mirza, A., Wang, X., Lipari, P., Seidel-Dugan, C., Hicklin, D. J., Bishop, W. R., Rindgen, D., Nomeir, A., Prosise, W., Reichert, P., Scapin, G., Strickland, C., & Doll, R. J. (2016). Discovery of Novel 3,3-Disubstituted Piperidines as Orally Bioavailable, Potent, and Efficacious HDM2-p53 Inhibitors. ACS medicinal chemistry letters, 7(3), 324-9. https://doi.org/10.1021/acsmedchemlett.5b00472
Bogen, Stéphane L, et al. "Discovery of Novel 3,3-Disubstituted Piperidines as Orally Bioavailable, Potent, and Efficacious HDM2-p53 Inhibitors." ACS medicinal chemistry letters vol. 7,3 (2016): 324-9. doi: https://doi.org/10.1021/acsmedchemlett.5b00472
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. 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. eCollection 2016 Mar 10. PMID: 26985323; PMCID: PMC4789661.
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ACS Med Chem Lett. 2016 Jan 20;7(3):324-9. doi: 10.1021/acsmedchemlett.5b00472. eCollection 2016 Mar 10.

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

ACS medicinal chemistry letters

Stéphane L Bogen, Weidong Pan, Craig R Gibeau, Brian R Lahue, Yao Ma, Latha G Nair, Elise Seigel, Gerald W Shipps, Yuan Tian, Yaolin Wang, Yinghui Lin, Ming Liu, Suxing Liu, Asra Mirza, Xiaoying Wang, Philip Lipari, Cynthia Seidel-Dugan, Daniel J Hicklin, W Robert Bishop, Diane Rindgen, Amin Nomeir, Winifred Prosise, Paul Reichert, Giovanna Scapin, Corey Strickland, Ronald J Doll

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 PMCID: PMC4789661 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

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