title: Discovery of Novel 3,3-Disubstituted Piperidines as Orally Bioavailable, Potent, and Efficacious HDM2-p53 Inhibitors.
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.
authors.affiliation: Discovery Chemistry, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Stéphane L
authors.initials: SL
authors.lastname: Bogen
authors.affiliation: Discovery Chemistry, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Weidong
authors.initials: W
authors.lastname: Pan
authors.affiliation: Discovery Chemistry, Merck Research Laboratories , Boston, Massachusetts 02115, United States.
authors.forename: Craig R
authors.initials: CR
authors.lastname: Gibeau
authors.affiliation: Discovery Chemistry, Merck Research Laboratories , Boston, Massachusetts 02115, United States.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Lahue
authors.affiliation: Discovery Chemistry, Merck Research Laboratories , Boston, Massachusetts 02115, United States.
authors.forename: Yao
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Discovery Chemistry, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Latha G
authors.initials: LG
authors.lastname: Nair
authors.affiliation: Discovery Chemistry, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Elise
authors.initials: E
authors.lastname: Seigel
authors.affiliation: Discovery Chemistry, Merck Research Laboratories , Boston, Massachusetts 02115, United States.
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Shipps
authors.affiliation: Discovery Chemistry, Merck Research Laboratories , Boston, Massachusetts 02115, United States.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Discovery Biology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Yaolin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Discovery Biology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Yinghui
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Discovery Biology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Ming
authors.initials: M
authors.lastname: Liu
authors.affiliation: Discovery Biology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Suxing
authors.initials: S
authors.lastname: Liu
authors.affiliation: Discovery Biology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Asra
authors.initials: A
authors.lastname: Mirza
authors.affiliation: Discovery Biology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Wang
authors.affiliation: Discovery Biology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Philip
authors.initials: P
authors.lastname: Lipari
authors.affiliation: Discovery Biology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Seidel-Dugan
authors.affiliation: Discovery Biology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Hicklin
authors.affiliation: Discovery Biology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: W Robert
authors.initials: WR
authors.lastname: Bishop
authors.affiliation: Pharmacokinetic, Pharmacodynamics and Drug Metabolism, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Diane
authors.initials: D
authors.lastname: Rindgen
authors.affiliation: Pharmacokinetic, Pharmacodynamics and Drug Metabolism, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Amin
authors.initials: A
authors.lastname: Nomeir
authors.affiliation: Structural Chemistry, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Winifred
authors.initials: W
authors.lastname: Prosise
authors.affiliation: Structural Chemistry, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Paul
authors.initials: P
authors.lastname: Reichert
authors.affiliation: Structural Chemistry, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Scapin
authors.affiliation: Structural Chemistry, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Corey
authors.initials: C
authors.lastname: Strickland
authors.affiliation: Discovery Chemistry, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Doll
keywords: HDM2; cancer; p53; protein−protein interaction