Open AccessPhenyl bioisosteres in medicinal chemistry: discovery of novel γ-secretase modulators as a potential treatment for Alzheimer's disease
Author(s) -
Hasane Ratni,
Karlheinz Baumann,
Peter Bellotti,
Xinlan A. F. Cook,
L G Green,
Thomas Luebbers,
Michael Reutlinger,
Antonia F. Stepan,
Walter Vifian
Publication year - 2021
Publication title -
rsc medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.754
H-Index - 55
ISSN - 2632-8682
DOI - 10.1039/d1md00043h
Subject(s) - bioisostere , moiety , drug discovery , piperidine , amyloid precursor protein secretase , chemistry , disease , pharmacology , medicine , combinatorial chemistry , stereochemistry , amyloid precursor protein , alzheimer's disease , biochemistry , chemical synthesis , in vitro
Phenyl rings are one of the most prevalent structural moieties in active pharmaceutical ingredients, even if they often contribute to poor physico-chemical properties. Herein, we propose the use of a bridged piperidine (BP) moiety as a phenyl bioisostere, which could also be seen as a superior phenyl alternative as it led to strongly improved drug like properties, in terms of solubility and lipophilicity. Additionally, this BP moiety compares favorably to the recently reported saturated phenyl bioisosteres. We applied this concept to our γ-secretase modulator (GSM) project for the potential treatment of Alzheimer's disease delivering clinical candidates.