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1.
Bioorg Med Chem Lett ; 28(3): 459-465, 2018 02 01.
Article in English | MEDLINE | ID: mdl-29254642

ABSTRACT

The synthesis and SAR of a novel class of spirobenzofuranpiperidinyl-derived alkanoic acids 6-34 as sphingosine S1P5 receptor agonists are described. The target compounds generally elicit high S1P5 receptor agonistic potencies and in general are selective against both S1P1 and S1P3 receptor subtypes. The key compound 32 shows a high bioavailability of 73% and a CNS/plasma ratio of 0.8 after oral administration in rats.


Subject(s)
Benzofurans/pharmacology , Receptors, Lysosphingolipid/agonists , Administration, Oral , Animals , Benzofurans/chemistry , Biological Availability , Dose-Response Relationship, Drug , Humans , Molecular Docking Simulation , Molecular Structure , Rats , Structure-Activity Relationship
2.
Bioorg Med Chem Lett ; 18(1): 188-93, 2008 Jan 01.
Article in English | MEDLINE | ID: mdl-18006307

ABSTRACT

We have investigated a series of 7-azaindoles as potential partial agonists of the alpha4beta2 nicotinic acetylcholine receptor (nAChR). Three series of 7-azaindole derivatives have been synthesized and evaluated for rat brain neuronal nicotinic receptor affinity and functional activity. Compound (+)-51 exhibited the most potent nAChR binding (Ki = 10 nM). Compound 30A demonstrated both moderate binding affinity and partial agonist potency, thus representing a promising lead for the indications of cognition and smoking cessation.


Subject(s)
Indoles/chemistry , Indoles/pharmacology , Nicotinic Agonists/chemistry , Nicotinic Agonists/pharmacology , Alkaloids/chemistry , Alkaloids/metabolism , Animals , Aza Compounds/chemical synthesis , Aza Compounds/chemistry , Aza Compounds/pharmacokinetics , Aza Compounds/pharmacology , Azocines/chemistry , Azocines/metabolism , Brain/metabolism , Indoles/chemical synthesis , Indoles/pharmacokinetics , Kinetics , Neurons/metabolism , Nicotinic Agonists/chemical synthesis , Nicotinic Agonists/pharmacokinetics , Quinolizines/chemistry , Quinolizines/metabolism , Radioligand Assay , Rats , Receptors, Nicotinic/chemistry , Receptors, Nicotinic/metabolism
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