ABSTRACT
The identification and optimization of a novel series of centrally efficacious gamma secretase modulators (GSMs) offering an alternative to the privileged aryl imidazole motif is described. Chiral bicyclic tetrahydroindazolyl amine substituted triazolopyridines were identified as structurally distinct novel series of GSMs. Representative compound BI-1408 ((R)-42) was demonstrated to be centrally efficacious in rats at a 30â¯mg/kg oral dose.
Subject(s)
Amyloid Precursor Protein Secretases/metabolism , Imidazoles/chemistry , Administration, Oral , Amyloid Precursor Protein Secretases/chemistry , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/metabolism , Animals , Bridged Bicyclo Compounds/chemistry , Cells, Cultured , Drug Design , Drug Evaluation, Preclinical , Female , Half-Life , Imidazoles/chemical synthesis , Imidazoles/pharmacokinetics , Inhibitory Concentration 50 , Neurons/cytology , Neurons/drug effects , Neurons/metabolism , Rats , Rats, Wistar , Structure-Activity RelationshipABSTRACT
A high-throughput screening campaign identified 4-((E)-styryl)-pyrimidin-2-ylamine (11) as a positive allosteric modulator of the metabotropic glutamate (mGlu) receptor subtype 4. An evaluation of the structure-activity relationships (SAR) of 11 is described and the efficacy of this compound in a haloperidol-induced catalepsy rat model following oral administration is presented.
Subject(s)
Pyrimidines/chemistry , Receptors, Metabotropic Glutamate/chemistry , Styrenes/chemistry , Administration, Oral , Allosteric Regulation , Animals , Catalepsy/chemically induced , Catalepsy/drug therapy , High-Throughput Screening Assays , Humans , Models, Animal , Motor Activity/physiology , Pyrimidines/chemical synthesis , Pyrimidines/therapeutic use , Rats , Rats, Sprague-Dawley , Receptors, Metabotropic Glutamate/metabolism , Structure-Activity Relationship , Styrenes/chemical synthesis , Styrenes/therapeutic useABSTRACT
Stimulation of the metabotropic glutamate receptor 4 (mGluR4) represents a promising new approach to the symptomatic treatment of the neurodegenerative disorder Parkinson's disease (PD). Preclinical models using both agonists and positive allosteric modulators of mGluR4 have demonstrated the potential for this receptor for the treatment of PD. The present article evaluates a recent patent filed by Addex Pharma S.A. claiming a novel series of mGluR4 positive allosteric modulators. Many of the examples disclosed are active at EC(50)'s < 500 nM.
