Novel S1P1 receptor agonists – Part 4: Alkylaminomethyl substituted aryl head groups

In a previous communication we reported on the discovery of alkylamino pyridine derivatives (e.g. 1) as a new class of potent, selective and efficacious S1P1 receptor (S1PR1) agonists. However, more detailed profiling revealed that this compound class is phototoxic in vitro. Here we describe a new c...

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Bibliographic Details
Published in:European journal of medicinal chemistry 2016-06, Vol.116, p.222-238
Main Authors: Lescop, Cyrille, Müller, Claus, Mathys, Boris, Birker, Magdalena, de Kanter, Ruben, Kohl, Christopher, Hess, Patrick, Nayler, Oliver, Rey, Markus, Sieber, Patrick, Steiner, Beat, Weller, Thomas, Bolli, Martin H.
Format: Article
Language:English
Subjects:
Aminomethyl benzene
Aminomethyl pyridine
Aminomethyl thiophene
Animals
Brain - metabolism
Drug Design
Immunomodulator
Lymphocyte count
Male
Phototoxicity
Pyridines - chemical synthesis
Pyridines - chemistry
Pyridines - pharmacokinetics
Pyridines - pharmacology
Rats
Rats, Wistar
Receptors, Lysosphingolipid - agonists
S1P1 receptor agonist
Structure-Activity Relationship
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Summary:In a previous communication we reported on the discovery of alkylamino pyridine derivatives (e.g. 1) as a new class of potent, selective and efficacious S1P1 receptor (S1PR1) agonists. However, more detailed profiling revealed that this compound class is phototoxic in vitro. Here we describe a new class of potent S1PR1 agonists wherein the exocyclic nitrogen was moved away from the pyridine ring (e.g. 11c). Further structural modifications led to the identification of novel alkylaminomethyl substituted phenyl and thienyl derivatives as potent S1PR1 agonists. These new alkylaminomethyl aryl compounds showed no phototoxic potential. Based on their in vivo efficacy and ability to penetrate the brain, the 5-alkyl-aminomethyl thiophenes appeared to be the most interesting class. Potent and selective S1PR1 agonist 20e, for instance, maximally reduced the blood lymphocyte count (LC) for 24 h after oral administration of 10 mg/kg to rat and its brain concentrations reached >500 ng/g over 24 h. [Display omitted] •A new class of potent and selective S1P1 receptor agonists was identified.•Alkylaminomethyl substituted aryl compounds exhibited nanomolar affinity for S1PR1.•These S1P1 receptor agonists, such as 20e, showed immunomodulatory efficacy after oral administration.•The new S1PR1 agonist series showed no in vitro phototoxicity.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2016.03.048