TY - JOUR
T1 - Multitarget-directed ligands combining cholinesterase and monoamine oxidase inhibition with histamine H3R antagonism for neurodegenerative diseases
AU - Bautista-Aguilera, Óscar M.
AU - Hagenow, Stefanie
AU - Palomino-Antolin, Alejandra
AU - Farré-Alins, Víctor
AU - Ismaili, Lhassane
AU - Joffrin, Pierre-Louis
AU - Jimeno, María L.
AU - Soukup, Ondřej
AU - Janočková, Jana
AU - Kalinowsky, Lena
AU - Proschak, Ewgenij
AU - Iriepa, Isabel
AU - Moraleda, Ignacio
AU - Schwed, Johannes S.
AU - Romero Martínez, Alejandro
AU - López-Muñoz, Francisco
AU - Chioua, Mourad
AU - Egea, Javier
AU - Ramsay, Rona R.
AU - Marco-Contelles, José
AU - Stark, Holger
N1 - J.M.C. thanks MINECO (SAF2012-33304 and SAF2015-65586-R). J.M.C., F.L.M., and A.R. thank UCJC for grants 2015-12, 2014-35, and 2015-21, respectively. J.E. thanks the Fondo de Investigaciones Sanitarias (FIS) (ISCIII/FEDER) (Programa Miguel Servet: CP14/00008 and PI16/00735) and Fundación Mutua Madrileña. O.S. and J.J. thank MHCZ-DRO (UHHK 00179906) for support. R.R.R., H.S., and J.M.C. acknowledge the EU COST Actions CM1103 and CM15135. E.P. and H.S. thank the German Research Foundation (DFG; PRO 1405/2-2, PRO 1405/4-1, SFB 1039 A07, and INST208/664-1).
PY - 2017/9/27
Y1 - 2017/9/27
N2 - The therapy of complex neurodegenerative diseases requires the development of multitarget-directed drugs (MTDs). Novel indole derivatives with inhibitory activity towards acetyl/butyrylcholinesterases and monoamine oxidases A/B as well as the histamine H3 receptor (H3R) were obtained by optimization of the neuroprotectant ASS234 by incorporating generally accepted H3R pharmacophore motifs. These small-molecule hits demonstrated balanced activities at the targets, mostly in the nanomolar concentration range. Additional in vitro studies showed antioxidative neuroprotective effects as well as the ability to penetrate the blood–brain barrier. With this promising in vitro profile, contilisant (at 1 mg kg−1 i.p.) also significantly improved lipopolysaccharide-induced cognitive deficits.
AB - The therapy of complex neurodegenerative diseases requires the development of multitarget-directed drugs (MTDs). Novel indole derivatives with inhibitory activity towards acetyl/butyrylcholinesterases and monoamine oxidases A/B as well as the histamine H3 receptor (H3R) were obtained by optimization of the neuroprotectant ASS234 by incorporating generally accepted H3R pharmacophore motifs. These small-molecule hits demonstrated balanced activities at the targets, mostly in the nanomolar concentration range. Additional in vitro studies showed antioxidative neuroprotective effects as well as the ability to penetrate the blood–brain barrier. With this promising in vitro profile, contilisant (at 1 mg kg−1 i.p.) also significantly improved lipopolysaccharide-induced cognitive deficits.
KW - Antioxidants
KW - Drug design
KW - Inhibitors
KW - Multitarget drugs
KW - Neurological agents
U2 - 10.1002/anie.201706072
DO - 10.1002/anie.201706072
M3 - Article
SN - 1433-7851
VL - 56
SP - 12765
EP - 12769
JO - Angewandte Chemie International Edition
JF - Angewandte Chemie International Edition
IS - 41
M1 - 201706072R2
ER -