Cyclic hydroxyamidines as amide isosteres: discovery of oxadiazolines and oxadiazines as potent and highly efficacious γ-secretase modulators in vivo

  • J Med Chem. 2012 Jan 12;55(1):489-502. doi: 10.1021/jm201407j.
Zhong-Yue Sun  1 ,  Theodros Asberom ,  Thomas Bara ,  Chad Bennett ,  Duane Burnett ,  Inhou Chu ,  John Clader ,  Mary Cohen-Williams ,  David Cole ,  Michael Czarniecki ,  James Durkin ,  Gioconda Gallo ,  William Greenlee ,  Hubert Josien ,  Xianhai Huang ,  Lynn Hyde ,  Nicholas Jones ,  Irina Kazakevich ,  Hongmei Li ,  Xiaoxiang Liu ,  Julie Lee ,  Malcolm Maccoss ,  Mihir B Mandal ,  Troy McCracken ,  Amin Nomeir ,  Robert Mazzola ,  Anandan Palani ,  Eric M Parker ,  Dmitri A Pissarnitski ,  Jun Qin ,  Lixin Song ,  Giuseppe Terracina ,  Monica Vicarel ,  Johannes Voigt ,  Ruo Xu ,  Lili Zhang ,  Qi Zhang ,  Zhiqiang Zhao ,  Xiaohong Zhu ,  Zhaoning Zhu
Affiliations
  • 1. Department of Medicinal Chemistry, Schering Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States. [email protected]
PMID: 22098494 DOI: 10.1021/jm201407j
Abstract

Cyclic hydroxyamidines were designed and validated as isosteric replacements of the amide functionality. Compounds with these structural motifs were found to be metabolically stable and to possess highly desirable pharmacokinetic profiles. These designs were applied in the identification of γ-secretase modulators leading to highly efficacious agents for reduction of central nervous system Aβ(42) in various animal models.