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.

Name
Email *

	Sorry, but the email address you supplied was invalid.