Open AccessDiscovery of Novel 3,3-Disubstituted Piperidines as Orally Bioavailable, Potent, and Efficacious HDM2-p53 Inhibitors
Author(s) -
Stéphane Bogen,
Weidong Pan,
Craig Gibeau,
Brian R. Lahue,
Yao Ma,
Latha G. Nair,
Elise Seigel,
Gerald W. Shipps,
Yuan Tian,
Yaolin Wang,
Yuan Lin,
Ming Liu,
Suxing Liu,
Asra Mirza,
Xiaoying Wang,
Philip Lipari,
Cynthia SeidelDugan,
Daniel J. Hicklin,
W. Robert Bishop,
Diane Rindgen,
Amin A. Nomeir,
W.W. Prosise,
Paul Reichert,
Giovanna Scapin,
Corey Strickland,
Ronald J. Doll
Publication year - 2016
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.5b00472
Subject(s) - piperidine , moiety , trifluoromethyl , chemistry , bioavailability , stereochemistry , ligand (biochemistry) , pharmacology , thiophene , computational biology , combinatorial chemistry , biochemistry , medicine , biology , organic chemistry , receptor , alkyl
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.