ABSTRACT
As part of our efforts to identify a suitable back-up compound to our recently disclosed mGlu5 positive allosteric modulator (PAM) clinical candidate VU0490551/JNJ-46778212, this letter details the investigation and challenges of a novel series of 6,7-dihydropyrazolo[1,5-a]pyrazin-4-one derivatives. From these efforts, compound 4k emerged as a potent and selective mGlu5 PAM displaying overall attractive in vitro (pharmacological and ADMET) and PK profiles combined with in vivo efficacy in preclinical models of schizophrenia. However, further advancement of the compound was precluded due to severely limiting CNS-related side-effects confirming the previously reported association between excessive mGlu5 activation and target-related toxicities.
Subject(s)
Allosteric Regulation/drug effects , Antipsychotic Agents/therapeutic use , Pyrazines/therapeutic use , Pyrazoles/therapeutic use , Receptor, Metabotropic Glutamate 5/metabolism , Schizophrenia/drug therapy , Animals , Antipsychotic Agents/chemistry , Antipsychotic Agents/pharmacokinetics , HEK293 Cells , Humans , Male , Pyrazines/chemistry , Pyrazines/pharmacokinetics , Pyrazoles/chemistry , Pyrazoles/pharmacokinetics , Rats, Sprague-Dawley , Schizophrenia/metabolismABSTRACT
We report the discovery and SAR of two novel series of imidazopyrimidinones and dihydroimidazopyrimidinones as metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulators (PAMs). Exploration of several structural features in the western and eastern part of the imidazopyrimidinone core and combinations thereof, revealed compound 4a as a mGlu5 PAM with good in vitro potency and efficacy, acceptable drug metabolism and pharmacokinetic (DMPK) properties and in vivo efficacy in an amphetamine-based model of psychosis. However, the presence of CNS-mediated adverse effects in preclinical species precluded any further in vivo evaluation.
Subject(s)
Antipsychotic Agents/chemistry , Heterocyclic Compounds, 2-Ring/chemistry , Imidazoles/chemistry , Pyrimidinones/chemistry , Receptor, Metabotropic Glutamate 5/chemistry , Allosteric Regulation , Animals , Antipsychotic Agents/chemical synthesis , Antipsychotic Agents/pharmacokinetics , Brain/metabolism , Drug Evaluation, Preclinical , Half-Life , Heterocyclic Compounds, 2-Ring/chemical synthesis , Heterocyclic Compounds, 2-Ring/pharmacokinetics , Humans , Imidazoles/chemical synthesis , Imidazoles/pharmacokinetics , Locomotion/drug effects , Microsomes, Liver/metabolism , Protein Binding , Pyrimidinones/chemical synthesis , Pyrimidinones/pharmacokinetics , Rats , Receptor, Metabotropic Glutamate 5/metabolism , Structure-Activity RelationshipABSTRACT
We report the continuation of a focused medicinal chemistry program aimed to further optimize a series of imidazo[1,2-a]pyrazines as a novel class of potent and selective phosphodiesterase 10A (PDE10A) inhibitors. In vitro and in vivo pharmacokinetic and pharmacodynamic evaluation allowed the selection of compound 25a for its assessment in preclinical models of psychosis. The evolution of our medicinal chemistry program, structure-activity relationship (SAR) analysis, as well as a detailed pharmacological profile for optimized lead 25a are described.
Subject(s)
Phosphodiesterase Inhibitors/chemical synthesis , Phosphoric Diester Hydrolases , Administration, Oral , Animals , Biological Availability , Disease Models, Animal , Phosphodiesterase Inhibitors/pharmacology , Phosphodiesterase Inhibitors/therapeutic use , Rats , Rats, Wistar , Schizophrenia/drug therapy , Structure-Activity RelationshipABSTRACT
We report the discovery of a series of imidazo[1,2-a]pyrazine derivatives as novel inhibitors of phosphodiesterase 10A (PDE10A). In a high-throughput screening campaign we identified the imidazopyrazine derivative 1, a PDE10A inhibitor with limited selectivity versus the other phosphodiesterases (PDEs). Subsequent investigation of 1 and replacement of the trimethoxyphenyl group by a (methoxyethyl)pyrazole moiety maintained PDE10A inhibition but enhanced selectivity against the other PDEs. Systematic examination and analysis of structure-activity and structure-property relationships resulted in the discovery of 2, an in vitro potent and selective inhibitor of PDE10A with high striatal occupancy of PDE10A, promising in vivo efficacy in different rodent behavioral models of schizophrenia, and a good pharmacokinetic profile in rats.
Subject(s)
Phosphodiesterase Inhibitors/chemical synthesis , Phosphoric Diester Hydrolases/drug effects , Schizophrenia/drug therapy , Administration, Oral , Animals , Drug Discovery , High-Throughput Screening Assays , Phosphodiesterase Inhibitors/pharmacology , Phosphodiesterase Inhibitors/therapeutic use , Rats , Structure-Activity RelationshipABSTRACT
Four terpenylnaphthoquinones were found to enhance the rate of superoxide production in the presence of ascorbate as detected from the superoxide dismutase (SOD)-inhibitable initial oxygen consumption rates. Initial rates of oxygen consumption in the presence of ascorbate plus quinone increase with an increase in the half-wave reduction potentials of the quinones. These quinones also enhance the rate of Cyt(III)c reduction by xanthine/xanthine oxidase (X/XO) in both air- and nitrogen-saturated aqueous solutions at pH 7.4. Maximum rates of Cyt(III)c reduction in nitrogen and oxygen-saturated solutions (V(max)), in the presence of X/XO, increase with an increase in the half-wave reduction potentials of the quinones. SOD inhibits Cyt(III)c reduction rates in the presence of these quinones and X/XO in a manner which is also dependent on the quinone half-wave redox potential. The relative antineoplastic activity of two of these quinones follows the order in rates of oxygen consumption or Cyt(III)c reduction. This is consistent with an antineoplastic action of these quinones through the mechanism of redox cycling or possible interference or inhibition of mitochondrial respiration.
