Optimization of Novel Aza-benzimidazolone mGluR2 PAMs with Respect to LLE and PK Properties and Mitigation of CYP TDI (original) (raw)
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We previously reported the discovery of 4-aryl-substituted pyridones with mGlu2 PAM activity starting from the HTS hit 5. In this article, we describe a different exploration from 5 that led to the discovery of a novel subseries of phenylpiperidine-substituted pyridones. The optimization strategy involved the introduction of different spacers between the pyridone core and the phenyl ring of 5. The fine tuning of metabolism and hERG followed by differentiation of advanced leads that were identified on the basis of PK profiles and in vivo potency converged on lead compound 36 (JNJ-40411813). Full in vitro and in vivo profiles indicate that 36 displayed an optimal interplay between potency, selectivity, favorable ADMET/PK and cardiovascular safety profile, and central EEG activity. Compound 36 has been investigated in the clinic for schizophrenia and anxious depression disorders.
Journal of Medicinal Chemistry, 2016
Positive allosteric modulators of the metabotropic glutamate 2 receptor have generated great interest in the last decade. There is mounting evidence of their potential as therapeutic agents in the treatment of multiple central nervous system disorders. We have previously reported substantial efforts leading to potent and selective mGlu2 PAMs. However, finding compounds with the optimal combination of in vitro potency and good drug-like properties has remained elusive, in part because of the hydrophobic nature of the allosteric binding site. Herein, we report on the lead optimization process to overcome the poor solubility inherent to the advanced lead 6. Initial prototypes already showed significant improvements in solubility while retaining good functional activity but displayed new liabilities associated to metabolism and hERG inhibition. Subsequent subtle modifications efficiently addressed those issues leading to the identification of compound 27 (JNJ-46356479). This new lead represents a more balanced profile that offers a significant improvement on the druglike attributes compared to previously reported leads.
The discovery and characterization of compound 48, a selective and in vivo active mGlu2 receptor positive allosteric modulator (PAM), are described. A key to the discovery was the rational exploration of the initial HTS hit 13 guided by an overlay model built with reported mGlu2 receptor PAM chemotypes. The initial weak in vitro activity of the hit 13 was quickly improved, although compounds still had suboptimal druglike properties. Subsequent modulation of the physicochemical properties resulted in compounds having a more balanced profile, combining good potency and in vivo pharmacokinetic properties. Final refinement by addressing cardiovascular safety liabilities led to the discovery of compound 48. Besides good potency, selectivity, and ADME properties, compound 48 displayed robust in vivo activity in a sleep−wake electroencephalogram (sw-EEG) assay consistent with mGlu2 receptor activation, in accordance with previous work from our laboratories.
Discovery of novel positive allosteric modulators of the metabotropic glutamate receptor 5 (mGlu5)
Bioorganic & Medicinal Chemistry Letters, 2011
Keywords: mGlu5 Metabotropic glutamate receptor 5 Glutamate NMDAr N-Methyl-D-aspartate receptor Positive allosteric modulator Schizophrenia a b s t r a c t Novel in vitro mGlu 5 positive allosteric modulators with good potency, solubility, and low lipophilicity are described. Compounds were identified which did not rely on the phenylacetylene and carbonyl functionalities previously observed to be required for in vitro activity. Investigation of the allosteric binding requirements of a series of dihydroquinolinone analogs led to phenylacetylene azachromanone 4 (EC 50 11.5 nM). Because of risks associated with potential metabolic and toxicological liabilities of the phenylacetylene, this moiety was successfully replaced with a phenoxymethyl group (27; EC 50 156.3 nM). Derivation of a second-generation of mGlu 5 PAMs lacking a ketone carbonyl resulted in azaindoline (33), azabenzimidazole (36), and N-methyl 8-azaoxazine (39) phenylacetylenes. By scoping nitrogen substituents and phenylacetylene replacements in 39, we identified phenoxymethyl 8-azaoxazine 47 (EC 50 50.1 nM) as a potent and soluble mGlu 5 PAM devoid of both undesirable phenylacetylene and carbonyl functionalities.
A series of N-propyl-8-chloro-6-substituted isoquinolones was identified as positive allosteric modula-tors of metabotropic glutamate receptor 2 (mGluR2 PAM) via high throughput screening (HTS). The subsequent synthesis and initial SAR exploration that led to the identification of compound 28 is described. The metabotropic glutamate type 2 receptor (mGluR2) belongs to the group II mGlu receptors that together with the group III are negatively coupled to adenylate cyclase activation. 1 Group II mGlu receptors reduce transmission at glutamatergic synapses in brain regions where excessive glutamatergic transmission may be implicated in the pathophysiology of anxiety and schizophrenia, such as the prefrontal cortex and hippocampus. It is therefore hypothesized that activation of group II mGlu receptors may provide anxiolytic and/or antipsychotic effects. 2 Interestingly, mGlu2 receptors are located presynaptically but outside of the active zone of glutamate release (in the periphery of the synapse) where they function to reduce excitatory glutamate neurotransmission in an activity-dependent manner. 3 There are recent clinical data that strengthen the rationale for group II receptor intervention as a treatment for schizophrenia. Thus LY2140023, the orally available prodrug of the mixed mGluR2/mGluR3 orthosteric agonist LY404039, showed improvement of both positive and negative symptoms in a double-blind placebo controlled study in schizophrenic patients. Moreover, treatment with LY2140023 was safe and well tolerated and in contrast to many of the current D 2 receptor antagonist antipsychotics LY2140023 did not affect prolactin levels nor induced extrapyrami-dal symptoms or weight gain. 4 While both LY2140023 (tested at single dose with optimal therapeutic dose still to be determined) and olanzapine significantly separated from placebo, there was no significant difference between the two treatment groups. 5 A second phase 2 study with LY2140023 failed to show clinical improvement in schizophrenic patients but was considered inconclusive due to a greater than expected placebo response (positive control olanzapine also did not separate from placebo). 6 On the other hand, there is evidence from studies in knockout mice that the mGlu2 receptor and not the mGlu3 receptor mediates the preclinical antipsychotic effects of the mixed mGluR2/mGluR3 agonists. 7,8 There is growing interest in identifying positive allosteric modu-lators (PAMs) of the mGluR2 which bind at an alternative site to the orthosteric endogenous agonist. This approach may offer several advantages, such as increasing mGluR2 signaling with greater selec-tivity compared to agonists, maintaining activity based on transient and dynamic release of glutamate without inducing over-activation or desensitization, as well as increasing the likelihood to identify 0960-894X/$-see front matter
3D-QSAR CoMFA study of benzoxazepine derivatives as mGluR5 positive allosteric modulators
Bioorganic & Medicinal Chemistry Letters, 2010
Positive allosteric modulation of the metabotropic glutamate receptor subtype 5 was studied by conducting a comparative molecular field analysis on 118 benzoxazepine derivatives. The model with the best predictive ability retained significant cross-validated correlation coefficients of q 2 =0.58 (r 2 =0.81) yielding a standard error of 0.20 in pEC 50 for this class of compounds. The subsequent contour maps highlight the structural features pertinent to the bioactivity values of benzoxazepines. Metabotropic glutamate receptor subtype 5 (mGluR 5) belongs to a family of G protein coupled receptors that play important roles in synaptic plasticity and other neuro-physiological and pathological processes 1-3. Prevailing cellular studies increasingly demonstrate a positive association between N-methyl D-aspartate (NMDA) receptors and mGluR 5 , suggesting that activation of mGluR 5 potentiates NMDA receptor function 4-6. Given evidence which suggests the role of hypofunction of NMDA receptors in the manifestation of the positive, negative, and cognitive symptoms of schizophrenia, potentiation of mGluR 5 , specifically through its allosteric binding site, is considered a possible avenue for ameliorating the symptoms of this debilitating disease 5, 7 .
Bioorganic & Medicinal Chemistry Letters, 2011
Based on SAR in the alkyne class of mGlu5 receptor negative allosteric modulators and a set of amide-based positive allosteric modulators, optimized substitution of the aryl 'b' ring was used to create substituted N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamides. Results from an mGlu5 receptor functional assay, using calcium fluorescence, revealed varying efficacies and potencies that provide evidence that subtle changes in compounds within a close structural class can have marked effects on functional activity including switches in modes of efficacy (i.e. negative to positive allosteric modulation). 1 This manuscript is dedicated to Professor James M. Cook on the occasion of his 65 th birthday.
Preclinical profile of a novel metabotropic glutamate receptor 5 positive allosteric modulator
European Journal of Pharmacology, 2011
Recent reports have indicated that patients with schizophrenia have a profound hypo-functionality of glutamatergic signaling pathways. Positive allosteric modulation of mGlu 5 receptor has been postulated to augment NMDA function and thereby alleviate the glutamatergic hypo-function observed in schizophrenic patients. Here we report the in vitro and in vivo characterization of CPPZ (1-(4-(2-chloro-4-fluorophenyl) piperazin-1-yl)-2-(pyridin-4-ylmethoxy)ethanone), a structurally novel positive allosteric modulator selective for mGlu 5 receptor. In HEK293 cells stably over-expressing human mGlu 5 receptor, CPPZ potentiates the intracellular calcium response elicited by a suboptimal concentration of the endogenous agonist glutamate. CPPZ does not have any intrinsic agonist activity and behaves functionally as a positive allosteric modulator. This is further supported by binding data, which demonstrate that CPPZ is able to displace the negative allosteric modulator MPEP but does not compete with the orthosteric ligand quisqualic acid. Instead, CPPZ enhances the binding of the orthosteric ligand. In native preparations, CPPZ potentiates calcium flux in rat cortical neurons stimulated with the group I agonist dihydroxyphenylglycine (DHPG). In addition, CPPZ modulates long-term potentiation in rat hippocampal slices, a process known to be NMDA dependent. In vivo, CPPZ reverses hyper locomotion triggered by the NMDA open channel blocker MK801 in CD1 mice. CPPZ was also able to reduce rat conditioned avoidance responding to electric shock. Both in vitro and in vivo data demonstrate that this novel compound acts as an mGlu 5 receptor positive allosteric modulator, which modulates NMDA dependent responses and suggests that the enhancement of mGlu 5 receptor activity may prove useful in the treatment of schizophrenia.
Molecular pharmacology, 2010
Modulators of metabotropic glutamate receptor subtype 5 (mGluR5) may provide novel treatments for multiple central nervous system (CNS) disorders, including anxiety and schizophrenia. Although compounds have been developed to better understand the physiological roles of mGluR5 and potential usefulness for the treatment of these disorders, there are limitations in the tools available, including poor selectivity, low potency, and limited solubility. To address these issues, we developed an innovative assay that allows simultaneous screening for mGluR5 agonists, antagonists, and potentiators. We identified multiple scaffolds that possess diverse modes of activity at mGluR5, including both positive and negative allosteric modulators (PAMs and NAMs, respectively). 3-Fluoro-5-(3-(pyridine-2-yl)-1,2,4-oxadiazol-5-yl)benzonitrile (VU0285683) was developed as a novel selective mGluR5 NAM with high affinity for the 2-methyl-6-(phenylethynyl)-pyridine (MPEP) binding site. VU0285683 had anxioly...