TY - JOUR
T1 - Navigating the Chemical Space of Multitarget-Directed Ligands
T2 - From Hybrids to Fragments in Alzheimer's Disease
AU - Prati, Federica
AU - Cavalli, Andrea
AU - Bolognesi, Maria Laura
N1 - This work was supported by MIUR—Ministero dell’Istruzione, dell’Università e della Ricerca—(PRIN—Progetti di ricerca di interesse nazionale—20103W4779) and the University of Bologna.
PY - 2016/4/8
Y1 - 2016/4/8
N2 - Multitarget drug discovery is one of the hottest topics and most active fields in the search for new molecules against Alzheimer's disease (AD). Over the last 20 years, many promising multitarget-directed ligands (MTDLs) have been identified and developed at a pre-clinical level. However, how to design them in a rational way remains the most fundamental challenge of medicinal chemists. This is related to the foundational question of achieving an optimized activity towards multiple targets of interest, while preserving drug-like properties. In this respect, large hybrid molecules and small fragments are poles apart. In this review article, our aim is to appraise what we have accomplished in the development of both hybrid- and fragment-like molecules directed to diverse AD targets (i.e., acetylcholinesterase, NMDA receptors, metal chelation, BACE-1 and GSK-3β). In addition, we attempt to highlight what are the persistent needs that deserve to be improved and cared for, with the ultimate goal of moving an MTDL to AD clinical studies.
AB - Multitarget drug discovery is one of the hottest topics and most active fields in the search for new molecules against Alzheimer's disease (AD). Over the last 20 years, many promising multitarget-directed ligands (MTDLs) have been identified and developed at a pre-clinical level. However, how to design them in a rational way remains the most fundamental challenge of medicinal chemists. This is related to the foundational question of achieving an optimized activity towards multiple targets of interest, while preserving drug-like properties. In this respect, large hybrid molecules and small fragments are poles apart. In this review article, our aim is to appraise what we have accomplished in the development of both hybrid- and fragment-like molecules directed to diverse AD targets (i.e., acetylcholinesterase, NMDA receptors, metal chelation, BACE-1 and GSK-3β). In addition, we attempt to highlight what are the persistent needs that deserve to be improved and cared for, with the ultimate goal of moving an MTDL to AD clinical studies.
KW - Bace-1 inhibitors
KW - Clioquinol
KW - Donepezil
KW - Galantamine
KW - GSK-3
KW - Inhibitors
KW - Memantine
KW - Multitarget drug discovery
UR - http://www.scopus.com/inward/record.url?scp=84968680168&partnerID=8YFLogxK
U2 - 10.3390/molecules21040466
DO - 10.3390/molecules21040466
M3 - Article
C2 - 27070562
AN - SCOPUS:84968680168
SN - 1420-3049
VL - 21
SP - 1
EP - 12
JO - Molecules
JF - Molecules
IS - 4
M1 - 466
ER -