ABSTRACT
A novel series of AMPAR positive modulators is described that were identified by high throughput screening. The molecules of the series have been optimized from a high quality starting point hit to afford excellent developability, tolerability, and efficacy profiles, leading to identification of a clinical candidate. Unusually for an ion channel target, this optimization was integrated with regular generation of ligand-bound crystal structures and uncovered a novel chemotype with a unique and highly conserved mode of interaction via a trifluoromethyl group.
Subject(s)
Indazoles/chemical synthesis , Receptors, AMPA/physiology , Allosteric Regulation , Animals , Calcium/metabolism , Crystallography, X-Ray , Dogs , High-Throughput Screening Assays , Humans , In Vitro Techniques , Indazoles/pharmacokinetics , Indazoles/pharmacology , Ligands , Macaca fascicularis , Male , Microsomes, Liver/metabolism , Models, Molecular , Molecular Conformation , Patch-Clamp Techniques , Protein Multimerization , Rats , Rats, Sprague-Dawley , Receptors, AMPA/chemistry , Recombinant Proteins/chemistry , Solubility , Structure-Activity Relationship , Swine , Swine, MiniatureABSTRACT
A series of AMPA receptor positive allosteric modulators has been optimized from poorly penetrant leads to identify molecules with excellent preclinical pharmacokinetics and CNS penetration. These discoveries led to 17i, a potent, efficacious CNS penetrant molecule with an excellent pharmacokinetic profile across preclinical species, which is well tolerated and is also orally bioavailable in humans.
Subject(s)
Indenes/chemical synthesis , Pyridines/chemical synthesis , Receptors, AMPA/physiology , Sulfonamides/chemical synthesis , Administration, Oral , Allosteric Regulation , Animals , Biological Availability , Blood Proteins/metabolism , Blood-Brain Barrier/metabolism , Callithrix , Cell Line , Crystallography, X-Ray , Dogs , Humans , Indenes/pharmacokinetics , Indenes/pharmacology , Macaca fascicularis , Male , Microsomes, Liver/metabolism , Models, Molecular , Protein Binding , Protein Structure, Tertiary , Pyridines/pharmacokinetics , Pyridines/pharmacology , Rats , Rats, Sprague-Dawley , Species Specificity , Stereoisomerism , Structure-Activity Relationship , Sulfonamides/pharmacokinetics , Sulfonamides/pharmacologyABSTRACT
Aberrant glutamatergic neurotransmission may underlie the pathogenesis of schizophrenia and metabotropic glutamate receptors (mGluRs) have been implicated in the disease. We have established the localization of the group III mGluR subtype, mGluR8, in the human body and investigated the biological effects of the selective mGluR8 agonist (S)-3,4-dicarboxyphenylglycine ((S)-3,4-DCPG) in schizophrenia-related animal models. The mGlu8 receptor has a widespread CNS distribution with expression observed in key brain regions associated with schizophrenia pathogenesis including the hippocampus. (S)-3,4-DCPG inhibited synaptic transmission and increased paired-pulse facilitation in rat hippocampal slices supporting the role of mGluR8 as a presynaptic autoreceptor. Using the rat Maximal Electroshock Seizure Threshold (MEST) test, (S)-3,4-DCPG (30 mg/kg, i.p.) reduced seizure activity confirming the compound to be centrally active following systemic administration. (S)-3,4-DCPG did not reverse (locomotor) hyperactivity induced by acute administration of phenylcyclidine (PCP, 1-32 mg/kg, i.p.) or amphetamine (3-30 mg/kg, i.p.) in Sprague-Dawley rats. However, 10 nmol (i.c.v.) (S)-3.4-DCPG did reverse amphetamine-induced hyperactivity in mice although it also inhibited spontaneous locomotor activity at this dose. In addition, mGluR8 null mutant mouse behavioral phenotyping revealed an anxiety-related phenotype but no deficit in sensorimotor gating. These data provide a potential role for mGluR8 in anxiety and suggest that mGluR8 may not be a therapeutic target for schizophrenia.
