Parallel synthesis of a series of potentially brain penetrant aminoalkyl benzoimidazoles.
Alpha7 agonists were identified via GOLD (CCDC) docking in the putative agonist binding site of an alpha7 homology model and a series of aminoalkyl benzoimidazoles was synthesised to obtain potentially brain penetrant drugs. The array was prepared starting from the reaction of ortho-fluoronitrobenzenes with a selection of diamines, followed by reduction of the nitro group to obtain a series of monoalkylated phenylene diamines. N,N'-Carbonyldiimidazole (CDI) mediated acylation, followed by a parallel automated work-up procedure, afforded the monoacylated phenylenediamines which were cyclised under acidic conditions. Parallel work-up and purification afforded the array products in good yields and purities with a robust parallel methodology which will be useful for other libraries. Screening for alpha7 activity revealed compounds with agonist activity for the receptor.
Micco
Iolanda
I
Siena Biotech S.p.A., Therapeutic Research, Via Fiorentina 1, Siena 53100, Italy.
Nencini
Arianna
A
Quinn
Joanna
J
Bothmann
Hendrick
H
Ghiron
Chiara
C
Padova
Alessandro
A
Papini
Silvia
S
D000478:Alkylation; D000586:Amination; D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002645:Chickens; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D064569:alpha7 Nicotinic Acetylcholine Receptor
D001562:Benzimidazoles; C579165:Chrna7 protein, rat; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D002118:Calcium