Publications by authors named "Jose Ignacio Andres"

30 Publications

  • Page 1 of 1

Discovery of N-(4-[F]Fluoro-5-methylpyridin-2-yl)isoquinolin-6-amine (JNJ-64326067), a New Promising Tau Positron Emission Tomography Imaging Tracer.

J Med Chem 2019 03 19;62(6):2974-2987. Epub 2019 Mar 19.

Janssen Research & Development, Janssen Pharmaceutica N. V. , Turnhoutseweg 30 , B-2340 Beerse , Belgium.

In Alzheimer's disease, the density and spread of aggregated tau protein track well with neurodegeneration and cognitive decline, making the imaging of aggregated tau a compelling biomarker. A structure-activity relationship exploration around an isoquinoline hit, followed by an exploration of tolerated fluorination positions, allowed us to identify 9 (JNJ-64326067), a potent and selective binder to aggregated tau with a favorable pharmacokinetic profile and no apparent off-target binding. This was confirmed in rat and monkey positron emission tomography studies using [F]9.
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http://dx.doi.org/10.1021/acs.jmedchem.8b01759DOI Listing
March 2019

Negishi coupling reactions with [C]CHI: a versatile method for efficient C-C bond formation.

Chem Commun (Camb) 2018 Apr;54(35):4398-4401

Radiochemistry and Nuclear Imaging, CIC biomaGUNE, Paseo Miramón 182, 20014 San Sebastián, Guipúzcoa, Spain.

Herein, we present a fast, efficient and general one-pot method for the synthesis of 11C-labelled compounds via the Negishi cross-coupling reaction. Our approach, based on the in situ formation of [11C]CH3ZnI and subsequent reaction with aryl halides or triflates, has proven efficient to synthesize [11C]thymidine, a biologically relevant compound with potential applications as a proliferation marker. Theoretical calculations have shown irreversible formation of a tetracoordinated nucleophilic 11C-Zn(ii) reagent and electronic requirements for an efficient Negishi coupling.
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http://dx.doi.org/10.1039/c8cc01540fDOI Listing
April 2018

Medicinal Chemistry strategies for PET tracer discovery.

Drug Discov Today Technol 2017 Nov 26;25:11-17. Epub 2017 Oct 26.

Neuroscience Therapeutic Area, Janssen Research & Development, Division of Janssen Pharmaceutica, NV, Turnhoutseweg 30, Beerse 2340, Belgium.

The detection of gamma rays, resulting from decay of positron emitting isotopes, allows exquisitely sensitive detection of probes radiolabeled with such isotopes. These probes can be designed for high affinity binding to specific molecular targets and be used as tools in the early development of drugs, particularly for neuropsychiatric disorders. Availability of novel tracers requires dedicated resources and selection assays. Many of the selection assays are similar to those used for discovery of clinical compounds, although the distribution and clearance of target specific radioligands requires different in vitro and in vivo methods and new derivatives.
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http://dx.doi.org/10.1016/j.ddtec.2017.10.002DOI Listing
November 2017

4-Methyl-6,7-dihydro-4H-triazolo[4,5-c]pyridine-Based P2X7 Receptor Antagonists: Optimization of Pharmacokinetic Properties Leading to the Identification of a Clinical Candidate.

J Med Chem 2017 06 25;60(11):4559-4572. Epub 2017 May 25.

Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121, United States.

The synthesis and preclinical characterization of novel 4-(R)-methyl-6,7-dihydro-4H-triazolo[4,5-c]pyridines that are potent and selective brain penetrant P2X7 antagonists are described. Optimization efforts based on previously disclosed unsubstituted 6,7-dihydro-4H-triazolo[4,5-c]pyridines, methyl substituted 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazines, and several other series lead to the identification of a series of 4-(R)-methyl-6,7-dihydro-4H-triazolo[4,5-c]pyridines that are selective P2X7 antagonists with potency at the rodent and human P2X7 ion channels. These novel P2X7 antagonists have suitable physicochemical properties, and several analogs have an excellent pharmacokinetic profile, good partitioning into the CNS and show robust in vivo target engagement after oral dosing. Improvements in metabolic stability led to the identification of JNJ-54175446 (14) as a candidate for clinical development. The drug discovery efforts and strategies that resulted in the identification of the clinical candidate are described herein.
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http://dx.doi.org/10.1021/acs.jmedchem.7b00408DOI Listing
June 2017

The value of PET ligand discovery to CNS drug development.

Future Med Chem 2017 03 6;9(4):351-356. Epub 2017 Mar 6.

Discovery Sciences, Janssen Research & Development, Janssen-Cilag S. A., C/Jarama 75A, 45007 Toledo, Spain.

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http://dx.doi.org/10.4155/fmc-2017-0018DOI Listing
March 2017

Preclinical Evaluation of F-JNJ64349311, a Novel PET Tracer for Tau Imaging.

J Nucl Med 2017 06 23;58(6):975-981. Epub 2017 Feb 23.

Laboratory for Radiopharmacy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium.

In this study, we have synthesized and evaluated F-JNJ64349311, a tracer with high affinity for aggregated tau (inhibition constant value, 8 nM) and high (≥500×) in vitro selectivity for tau over β-amyloid, in comparison with the benchmark compound F-AV1451 (F-T807) in mice, rats, and a rhesus monkey. In vitro binding characteristics were determined for Alzheimer's disease, progressive supranuclear palsy, and corticobasal degeneration patient brain tissue slices using autoradiography studies. Ex vivo biodistribution studies were performed in mice. Radiometabolites were quantified in the brain and plasma of mice and in the plasma of a rhesus monkey using high-performance liquid chromatography. Dynamic small-animal PET studies were performed in rats and a rhesus monkey to evaluate tracer pharmacokinetics in the brain. Mouse biodistribution studies showed moderate initial brain uptake and rapid brain washout. Radiometabolite analyses after injection of F-JNJ64349311 in mice showed the presence of a polar radiometabolite in plasma, but not in the brain. Semiquantitative autoradiography studies on postmortem tissue sections of human Alzheimer's disease brains showed highly displaceable binding to tau-rich regions. No specific binding was, however, found on human progressive supranuclear palsy and corticobasal degeneration brain slices. Small-animal PET scans of Wistar rats revealed moderate initial brain uptake (SUV, ∼1.5 at 1 min after injection) and rapid brain washout. Gradual bone uptake was, however, also observed. Blocking and displacement did not affect brain time-activity curves, suggesting no off-target specific binding of the tracer in the healthy rat brain. A small-animal PET scan of a rhesus monkey revealed moderate initial brain uptake (SUV, 1.9 at 1 min after injection) with a rapid washout. In the monkey, no bone uptake was detected during the 120-min scan. This biologic evaluation suggests that F-JNJ64349311 is a promising tau PET tracer candidate, with a favorable pharmacokinetic profile, as compared with F-AV1451.
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http://dx.doi.org/10.2967/jnumed.116.185199DOI Listing
June 2017

Discovery of N-(Pyridin-4-yl)-1,5-naphthyridin-2-amines as Potential Tau Pathology PET Tracers for Alzheimer's Disease.

J Med Chem 2017 02 10;60(4):1272-1291. Epub 2017 Feb 10.

Neuroscience Biology, Janssen Research & Development, Janssen Pharmaceutica N. V. , Turnhoutseweg 30, B-2340 Beerse, Belgium.

A mini-HTS on 4000 compounds selected using 2D fragment-based similarity and 3D pharmacophoric and shape similarity to known selective tau aggregate binders identified N-(6-methylpyridin-2-yl)quinolin-2-amine 10 as a novel potent binder to human AD aggregated tau with modest selectivity versus aggregated β-amyloid (Aβ). Initial medicinal chemistry efforts identified key elements for potency and selectivity, as well as suitable positions for radiofluorination, leading to a first generation of fluoroalkyl-substituted quinoline tau binding ligands with suboptimal physicochemical properties. Further optimization toward a more optimal pharmacokinetic profile led to the discovery of 1,5-naphthyridine 75, a potent and selective tau aggregate binder with potential as a tau PET tracer.
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http://dx.doi.org/10.1021/acs.jmedchem.6b01173DOI Listing
February 2017

Tau Positron Emission Tomography Imaging.

Cold Spring Harb Perspect Biol 2017 May 1;9(5). Epub 2017 May 1.

Janssen Research and Development, Discovery Sciences, Janssen-Cilag S.A., 45007 Toledo, Spain.

Alzheimer's disease (AD) is a chronic neurodegenerative disorder and the most common cause of dementia among the elderly population. The good correlation between the density and neocortical spread of neurofibrillary tangles (NFTs) and the severity of cognitive impairment offers an opportunity to use a noninvasive imaging technique such as positron emission tomography (PET) for early diagnosis and staging of the disease. PET imaging of NFTs holds promise not only as a diagnostic tool but also because it may enable the development of disease-modifying therapeutics for AD. In this review, we focus on the structural diversity of tau PET tracers, the challenges related to identifying high-affinity and highly selective NFT ligands, and recent progress in the clinical development of tau PET radioligands.
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http://dx.doi.org/10.1101/cshperspect.a023721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5411699PMC
May 2017

What We Observe In Vivo Is Not Always What We See In Vitro: Development and Validation of 11C-JNJ-42491293, A Novel Radioligand for mGluR2.

J Nucl Med 2017 Jan 28;58(1):110-116. Epub 2016 Jul 28.

Janssen Research & Development, Janssen Pharmaceutica Nevada, Beerse, Belgium.

Positive allosteric modulators (PAM) of metabotropic glutamate receptor 2 (mGluR2) are a potential therapy for anxiety, schizophrenia, and addiction. Aside from pathophysiologic imaging studies, an mGluR2 PET tracer would enable confirmation of sufficient central target engagement and assist dose selection for proof-of-concept studies of PAM compounds. C-JNJ-42491293, a novel high-affinity radioligand (human 50% inhibitory concentration = 9.6 nM) for the PAM site of mGluR2, was evaluated as a selective mGluR2 PAM PET tracer.

Methods: In vitro and ex vivo autoradiography binding experiments in Wistar and in mGluR2 knockout and wildtype rats as well as in vivo biodistribution and brain PET imaging studies in wildtype and mGluR2 knockout rats in a primate and in humans were performed.

Results: In vitro binding studies and in vivo imaging studies in Wistar rats showed moderate brain uptake, with a distribution pattern fully consistent with the reported intracerebral distribution of mGluR2. Given these promising findings, biodistribution, dosimetry, and brain kinetic modeling of C-JNJ-42491293 were determined in humans. Because of an unexpected high myocardial retention, additional C-JNJ-42491293 imaging studies were performed in recently available mGluR2 knockout and wildtype rats and in a monkey using a structurally distinct mGluR2 PAM ligand with affinity for the same site, demonstrating off-target binding in vivo that could not have been anticipated from previous in vitro experiments. To date, the target of this non-mGluR2 tracer binding remains unknown.

Conclusion: On the basis of in vivo selectivity issues suggested by human distribution and demonstrated in knockout rat models, C-JNJ-42491293 was considered unsuitable as a specific PET ligand for in vivo imaging of mGluR2. These results emphasize the importance of elaborated in vitro/in vivo comparative studies and, when available, validation with knockout animal models or structurally distinct ligands with affinity for the same site, in radiotracer development.
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http://dx.doi.org/10.2967/jnumed.116.176628DOI Listing
January 2017

Preclinical Evaluation of a P2X7 Receptor-Selective Radiotracer: PET Studies in a Rat Model with Local Overexpression of the Human P2X7 Receptor and in Nonhuman Primates.

J Nucl Med 2016 09 19;57(9):1436-41. Epub 2016 May 19.

Laboratory for Radiopharmacy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium

Unlabelled: The P2X7 receptor (P2X7R) orchestrates neuroinflammation, and this is the basis for an increased interest in the development of antagonists inhibiting P2X7R function in the brain. This study provides the preclinical evaluation of (11)C-JNJ-54173717, a PET tracer for P2X7R in both rats and nonhuman primates.

Methods: (11)C-JNJ-54173717 is a high-affinity radiotracer for the human P2X7R (hP2X7R). Biodistribution and radiometabolite studies were performed. Viral vectors encoding either enhanced green fluorescent protein-hP2X7R or 3flag-hP2X7R were engineered and validated in cell culture. hP2X7R was regionally overexpressed in the rat striatum after stereotactic injection of viral vectors. Dynamic small-animal PET studies were performed in vector-injected rats and in healthy monkeys using (11)C-JNJ-54173717.

Results: The affinity of JNJ-54173717 was 1.6 ± 0.1 nM in a rat cortex P2X7R membrane binding assay. In a functional assay at the recombinant human and rat P2X7R orthologs, the half maximal inhibitory concentration (IC50) of JNJ-54173717 was 4.2 ± 0.01 nM and 7.6 ± 0.01 nM, respectively. The rat biodistribution study showed that (11)C-JNJ-54173717 crossed the blood-brain barrier and was cleared from plasma mainly via the hepatobiliary pathway. A polar radiometabolite was found in rat plasma. No radiometabolites were detected in rat brain. Dynamic small-animal PET showed binding of (11)C-JNJ-54173717 in the striatum expressing hP2X7R, with rapid washout from the noninjected control striatum and other brain regions. Likewise, (11)C-JNJ-54173717 PET signal was blocked by a chemically distinct P2X7R ligand, indicating specific binding to P2X7R in the monkey brain.

Conclusion: JNJ-54173717 is a high-affinity P2X7R antagonist. An animal rat model stably expressing hP2X7R was developed and validated, identifying favorable characteristics for (11)C-JNJ-54173717 as a PET radioligand for in vivo visualization of hP2X7R. (11)C-JNJ-54173717 selectively visualized P2X7R in the monkey brain, and this radioligand will be further evaluated in a clinical setting to study P2X7R expression levels in neurodegenerative disorders.
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http://dx.doi.org/10.2967/jnumed.115.169995DOI Listing
September 2016

Novel methyl substituted 1-(5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanones are P2X7 antagonists.

Bioorg Med Chem Lett 2015 Aug 9;25(16):3157-63. Epub 2015 Jun 9.

Janssen Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, United States. Electronic address:

The optimization efforts that led to a novel series of methyl substituted 1-(5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanones that are potent rat and human P2X7 antagonists are described. These efforts resulted in the discovery of compounds with good drug-like properties that are capable of high P2X7 receptor occupancy in rat following oral administration, including compounds 7n (P2X7 IC50 = 7.7 nM) and 7u (P2X7 IC50 =7 .7 nM). These compounds are expected to be useful tools for characterizing the effects of P2X7 antagonism in models of depression and epilepsy, and several of the compounds prepared are candidates for effective P2X7 PET tracers.
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http://dx.doi.org/10.1016/j.bmcl.2015.06.004DOI Listing
August 2015

Pyrido[4,3-e][1,2,4]triazolo[4,3-a]pyrazines as Selective, Brain Penetrant Phosphodiesterase 2 (PDE2) Inhibitors.

ACS Med Chem Lett 2015 Mar 15;6(3):282-6. Epub 2015 Jan 15.

Neuroscience-Medicinal Chemistry, Janssen Research & Development, Janssen-Cilag S.A. , C/Jarama 75, 45007 Toledo, Spain.

A novel series of pyrido[4,3-e][1,2,4]triazolo[4,3-a]pyrazines is reported as potent PDE2/PDE10 inhibitors with drug-like properties. Selectivity for PDE2 was obtained by introducing a linear, lipophilic moiety on the meta-position of the phenyl ring pending from the triazole. The SAR and protein flexibility were explored with free energy perturbation calculations. Rat pharmacokinetic data and in vivo receptor occupancy data are given for two representative compounds 6 and 12.
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http://dx.doi.org/10.1021/ml500463tDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4360147PMC
March 2015

Tau Positron Emission Tomography (PET) Imaging: Past, Present, and Future.

J Med Chem 2015 Jun 25;58(11):4365-82. Epub 2015 Feb 25.

∥Discovery Sciences, Janssen Research and Development, a Division of Janssen-Cilag, Jarama 75, 45007 Toledo, Spain.

Alzheimer's disease (AD) is a chronic neurodegenerative disorder and the most common cause of dementia among the elderly population. The good correlation of the density and neocortical spread of neurofibrillary tangles (NFTs) with clinical AD disease progression offers an opportunity for the early diagnosis and staging using a noninvasive imaging technique such as positron emission tomography (PET). Thus, PET imaging of NFTs not only holds promise as a diagnostic tool but also may enable the development of disease modifying therapeutics for AD. In this review, we focus on the structural diversity of tau PET tracers, the challenges related to the identification of high affinity and highly selective NFT ligands, and recent progress in the clinical development of tau PET radioligands.
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http://dx.doi.org/10.1021/jm5017544DOI Listing
June 2015

Structure-Based Design of a Potent, Selective, and Brain Penetrating PDE2 Inhibitor with Demonstrated Target Engagement.

ACS Med Chem Lett 2014 Sep 22;5(9):1049-53. Epub 2014 Jul 22.

Neuroscience Medicinal Chemistry, Janssen Research & Development, Janssen-Cilag S.A. , C/Jarama 75, 45007 Toledo, Spain.

Structure-guided design led to the identification of the novel, potent, and selective phosphodiesterase 2 (PDE2) inhibitor 12. Compound 12 demonstrated a >210-fold selectivity versus PDE10 and PDE11 and was inactive against all other PDE family members up to 10 μM. In vivo evaluation of 12 provided evidence that it is able to engage the target and to increase cGMP levels in relevant brain regions. Hence, 12 is a valuable tool compound for the better understanding of the role of PDE2 in cognitive impairment and other central nervous system related disorders.
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http://dx.doi.org/10.1021/ml500262uDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4160764PMC
September 2014

Discovery of 1-butyl-3-chloro-4-(4-phenyl-1-piperidinyl)-(1H)-pyridone (JNJ-40411813): a novel positive allosteric modulator of the metabotropic glutamate 2 receptor.

J Med Chem 2014 Aug 28;57(15):6495-512. Epub 2014 Jul 28.

Neuroscience Medicinal Chemistry, Janssen Research & Development, Janssen-Cilag S.A. , C/Jarama 75, 45007 Toledo, Spain.

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.
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http://dx.doi.org/10.1021/jm500496mDOI Listing
August 2014

Synthesis and biological evaluation of carbon-11 and fluorine-18 labeled tracers for in vivo visualization of PDE10A.

Nucl Med Biol 2014 Sep 24;41(8):695-704. Epub 2014 May 24.

Laboratory for Radiopharmacy, KU Leuven, Belgium; MoSAIC, Molecular Small Animal Imaging Centre, KU Leuven, Belgium. Electronic address:

Introduction: In vivo visualization of PDE10A using PET provides a tool to evaluate the role of PDE10A in various neuropsychiatric diseases and can also be useful in the clinical evaluation of PDE10A inhibitor drug candidates. We evaluated several carbon-11 and fluorine-18 labeled PDE10A inhibitors as potential PDE10A PET radioligands.

Materials & Methods: [(11)C]MP10, [(11)C]JNJ42071965 and four other tracers were developed. Their biodistribution was evaluated in rats. Rat plasma and brain radiometabolites were quantified. Baseline microPET imaging was performed in normal rats and PDE10A knockout (KO) and wild-type (WT) mice. Blocking and displacement studies were conducted. The selectivity of the tracer binding was further studied in an ex vivo autoradiography experiment in PDE10A KO and WT mice.

Results: Biodistribution showed brain uptake for all tracers in the striatum and wash-out from the cerebellum. [(11)C]1 ((11)C-MP10) had the highest specific uptake index (striatum (S) vs. cerebellum (C) ratios (S/C)-1) at 60 min (7.4). [(11)C]5 ([(11)C]JNJ42071965) had a high index at the early time points (1.0 and 3.7 at 2 and 30 min p.i., respectively). The affinity of [(11)C]4, [(18)F]3 and [(18)F]6 was too low to visualize PDE10A using microPET. [(11)C] 2 showed a specific binding, while kinetics of [(11)C]1 were too slow. [(11)C]5 reached equilibrium after 10 min (uptake index=1.2). Blocking and displacement experiments in rats and baseline imaging in PDE10A KO mice showed specific and reversible binding of [(11)C]5 to PDE10A.

Conclusions: We successfully radiolabeled and evaluated six radiotracers for their potential to visualize PDE10A in vivo. While [(11)C]1 had the highest striatal specific uptake index, its slow kinetics likely compromise clinical use of this tracer. [(11)C]5 has a relatively high striatum-to-background ratio and fast kinetic profile, which makes it a valuable carbon-11 alternative.
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http://dx.doi.org/10.1016/j.nucmedbio.2014.05.138DOI Listing
September 2014

Pharmacological characterization of JNJ-40068782, a new potent, selective, and systemically active positive allosteric modulator of the mGlu2 receptor and its radioligand [3H]JNJ-40068782.

J Pharmacol Exp Ther 2013 Sep 13;346(3):514-27. Epub 2013 Jun 13.

Janssen Research and Development, Beerse, Belgium.

Modulation of the metabotropic glutamate type 2 (mGlu2) receptor is considered a promising target for the treatment of central nervous system diseases such as schizophrenia. Here, we describe the pharmacological properties of the novel mGlu2 receptor positive allosteric modulator (PAM) 3-cyano-1-cyclopropylmethyl-4-(4-phenyl-piperidin-1-yl)-pyridine-2(1H)-one (JNJ-40068782) and its radioligand [(3)H]JNJ-40068782. In guanosine 5'-O-(3-[(35)S]thio)triphosphate binding, JNJ-40068782 produced a leftward and upward shift in the glutamate concentration-effect curve at human recombinant mGlu2 receptors. The EC50 of JNJ-40068782 for potentiation of an EC20-equivalent concentration of glutamate was 143 nM. Although JNJ-40068782 did not affect binding of the orthosteric antagonist [(3)H]2S-2-amino-2-(1S,2S-2-carboxycyclopropyl-1-yl)-3-(xanth-9-yl)propanoic acid (LY-341495), it did potentiate the binding of the agonist [(3)H](2S,2'R,3'R)-2-(2',3'-dicarboxylcyclopropyl)glycine (DCG-IV), demonstrating that it can allosterically affect binding at the agonist recognition site. The binding of [(3)H]JNJ-40068782 to human recombinant mGlu2 receptors in Chinese hamster ovary cells and rat brain receptors was saturable with a KD of ∼10 nM. In rat brain, the anatomic distribution of [(3)H]JNJ-40068782 was consistent with mGlu2 expression previously described and was most abundant in cortex and hippocampus. The ability of structurally unrelated PAMs to displace [(3)H]JNJ-40068782 suggests that PAMs may bind to common determinants within the same site. It is noteworthy that agonists also increased the binding affinity of [(3)H]JNJ-40068782. JNJ-40068782 influenced rat sleep-wake organization by decreasing rapid eye movement sleep with a lowest active dose of 3 mg/kg PO. In mice, JNJ-40068782 reversed phencyclidine-induced hyperlocomotion with an ED50 of 5.7 mg/kg s.c. Collectively, the present data demonstrate that JNJ-40068782 has utility in investigating the potential of mGlu2 modulation for the treatment of diseases characterized by disturbed glutamatergic signaling and highlight the value of [(3)H]JNJ-40068782 in exploring allosteric binding.
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http://dx.doi.org/10.1124/jpet.113.204990DOI Listing
September 2013

Discovery of a new series of [1,2,4]triazolo[4,3-a]quinoxalines as dual phosphodiesterase 2/phosphodiesterase 10 (PDE2/PDE10) inhibitors.

Bioorg Med Chem Lett 2013 Feb 1;23(3):785-90. Epub 2012 Dec 1.

Janssen Research & Development, Medicinal Chemistry, Janssen-Cilag S.A., C/Jarama 75, 45007 Toledo, Spain.

The synthesis, preliminary evaluation and structure-activity relationship (SAR) of a series of 1-aryl-4-methyl[1,2,4]triazolo[4,3-a]quinoxalines as dual phosphodiesterase 2/phosphodiesterase 10 (PDE2/PDE10) inhibitors are described. From this investigation compound 31 was identified, showing good combined potency, acceptable brain uptake and high selectivity for both PDE2 and PDE10 enzymes. Compound 31 was subjected to a microdosing experiment in rats, showing preferential distribution in brain areas where both PDE2 and PDE10 are highly expressed. These promising results may drive the further development of highly potent combined PDE2/PDE10 inhibitors, or even of selective inhibitors of PDE2 and/or PDE10.
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http://dx.doi.org/10.1016/j.bmcl.2012.11.077DOI Listing
February 2013

Discovery of 3-cyclopropylmethyl-7-(4-phenylpiperidin-1-yl)-8-trifluoromethyl[1,2,4]triazolo[4,3-a]pyridine (JNJ-42153605): a positive allosteric modulator of the metabotropic glutamate 2 receptor.

J Med Chem 2012 Oct 16;55(20):8770-89. Epub 2012 Oct 16.

Neuroscience Medicinal Chemistry, Janssen Research & Development, Janssen-Cilag S.A., Jarama 75, 45007 Toledo, Spain.

Advanced leads from a series of 1,2,4-triazolo[4,3-a]pyridines with mGlu2 receptor PAM activity are reported. By modification of the analogous imidazo[1,2-a]pyridine series, the newly reported leads have improved potency, in vitro ADMET, and hERG as well as good in vivo PK profile. The optimization of the series focused on improving metabolic stability while controlling lipophilicity by introducing small modifications to the scaffold substituents. Analysis of this series combined with our previously reported mGlu2 receptor PAMs showed how lipophilic ligand efficiency was improved during the course of the program. Among the best compounds, example 20 (JNJ-42153605) showed a central in vivo efficacy by inhibition of REM sleep state at a dose of 3 mg/kg po in the rat sleep-wake EEG paradigm, a phenomenon shown earlier to be mGlu2 mediated. In mice, compound 20 reversed PCP-induced hyperlocomotion with an ED₅₀ of 5.4 mg/kg sc, indicative of antipsychotic activity.
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http://dx.doi.org/10.1021/jm3010724DOI Listing
October 2012

Synthesis, evaluation, and radiolabeling of new potent positive allosteric modulators of the metabotropic glutamate receptor 2 as potential tracers for positron emission tomography imaging.

J Med Chem 2012 Oct 11;55(20):8685-99. Epub 2012 Oct 11.

Medicinal Chemistry, Janssen Research & Development , Janssen-Cilag S.A., C/Jarama 75, 45007 Toledo, Spain.

The synthesis and in vitro and in vivo evaluation of a new series of 7-(phenylpiperidinyl)-1,2,4-triazolo[4,3-a]pyridines, which were conveniently radiolabeled with carbon-11, as potential positron emission tomography (PET) radiotracers for in vivo imaging of the allosteric binding site of the metabotropic glutamate (mGlu) receptor subtype 2 are described. The synthesized compounds proved to be potent and selective positive allosteric modulators (PAMs) of the mGlu receptor 2 (mGluR2) in a [³⁵S]GTPγS binding assay and were able to displace an mGluR2 PAM radioligand, which we had previously developed, with IC₅₀ values in the low nanomolar range. The most promising candidates were radiolabeled and subjected to biodistribution studies and radiometabolite analysis in rats. Preliminary small-animal PET (μPET) studies in rats indicated that [¹¹C]20f binds specifically and reversibly to an mGluR2 allosteric site, strongly suggesting that it is a promising candidate for PET imaging of mGluR2 in the brain.
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http://dx.doi.org/10.1021/jm300912kDOI Listing
October 2012

Recent advances in positron emission tomography (PET) radiotracers for imaging phosphodiesterases.

Curr Top Med Chem 2012 ;12(11):1224-36

Community of Research Excellence & Advanced Technology (CREATe), PET Ligand Discovery, Janssen Research & Development, Janssen-Cilag S.A., C/ Jarama 75, 45007 Toledo, Spain.

Phosphodiesterases (PDEs) are a family of enzymes that metabolically inactivate the second messengers 3',5'- cyclic adenosine monophosphate (cAMP) and/or 3',5'-cyclic guanosine monophosphate (cGMP). These two messengers regulate the extracellular signal from the plasma membrane G protein-coupled receptors (GPCRs) to the intracellular effector proteins, hence modulating a wide variety of biological processes both in the central nervous system (CNS) and peripheral tissues. Although there are many radiotracers available for positron emission tomography (PET) studies of different receptors, there are just a few tracers available for imaging studies of second messenger systems. The first reported PDE PET ligands were the 11C-labeled versions of the PDE4 inhibitors rolipram and Ro 20-1724, and, to date, PET imaging studies in human subjects have only been reported with [11C]rolipram. As a consequence of the growing interest in identifying selective PDE inhibitors as potential new therapeutic agents, new PET radiotracers for imaging specific PDEs have been described in literature as well. This article highlights these efforts on the design and evaluation of novel PET radioligands for in vivo imaging of PDEs.
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http://dx.doi.org/10.2174/156802612800672853DOI Listing
March 2013

Discovery of 1,4-disubstituted 3-cyano-2-pyridones: a new class of positive allosteric modulators of the metabotropic glutamate 2 receptor.

J Med Chem 2012 Mar 24;55(5):2388-405. Epub 2012 Feb 24.

Neuroscience Medicinal Chemistry, Janssen Research & Development, Janssen-Cilag S.A., Jarama 75, 45007-Toledo, Spain.

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.
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http://dx.doi.org/10.1021/jm2016864DOI Listing
March 2012

Imidazo[1,2-a]pyridines: orally active positive allosteric modulators of the metabotropic glutamate 2 receptor.

J Med Chem 2012 Mar 1;55(6):2688-701. Epub 2012 Mar 1.

Neuroscience Medicinal Chemistry, Janssen Research & Development, Janssen-Cilag S.A., Jarama 75, 45007-Toledo, Spain.

Advanced leads of an imidazopyridine series of positive allosteric modulators of the metabotropic glutamate 2 (mGlu2) receptor are reported. The optimization of in vitro ADMET and in vivo pharmacokinetic properties led to the identification of 27o. With good potency and selectivity for the mGlu2 receptor, 27o affected sleep-wake architecture in rats after oral treatment, which we have previously shown to be indicative of mGlu2 receptor-mediated central activity.
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http://dx.doi.org/10.1021/jm201561rDOI Listing
March 2012

Synthesis, in vivo occupancy, and radiolabeling of potent phosphodiesterase subtype-10 inhibitors as candidates for positron emission tomography imaging.

J Med Chem 2011 Aug 2;54(16):5820-35. Epub 2011 Aug 2.

Medicinal Chemistry, Janssen Research & Development, Janssen-Cilag SA, C/Jarama 75, 45007 Toledo, Spain.

We have recently reported the phosphodiesterase 10A (PDE10A) inhibitor 2-[4-[1-(2-[(18)F]fluoroethyl)-4-pyridin-4-yl-1H-pyrazol-3-yl]-phenoxymethyl]-quinoline ([(18)F]1a) as a promising candidate for in vivo imaging using positron emission tomography (PET). We now describe the synthesis and biological evaluation of a series of related pyridinyl analogues that exhibit high potency and selectivity as PDE10A inhibitors. The most interesting compounds were injected in rats to measure their levels of PDE10A occupancy through an in vivo occupancy assay. The 3,5-dimethylpyridine derivative 3 and the 5-methoxypyridine derivative 4 showed a comparable level of occupancy to that of 1a. Because these derivatives showed lower in vitro activity and are slightly less lipophilic than 1a, we hypothesized that they could behave as better PET imaging ligands. Compounds [(18)F]3, [(18)F]4, and [(11)C]4 were radiosynthesized and subjected to biodistribution studies in rats for a preliminary evaluation as candidate PET radioligands for in vivo imaging of PDE10A in the brain.
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http://dx.doi.org/10.1021/jm200536dDOI Listing
August 2011

New positive allosteric modulators of the metabotropic glutamate receptor 2 (mGluR2): identification and synthesis of N-propyl-8-chloro-6-substituted isoquinolones.

Bioorg Med Chem Lett 2011 Feb 21;21(3):971-6. Epub 2010 Dec 21.

Medicinal Chemistry, Janssen Research & Development, Janssen-Cilag SA, Toledo, Spain.

A series of N-propyl-8-chloro-6-substituted isoquinolones was identified as positive allosteric modulators 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.
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http://dx.doi.org/10.1016/j.bmcl.2010.12.048DOI Listing
February 2011

Discovery of 1,5-disubstituted pyridones: a new class of positive allosteric modulators of the metabotropic glutamate 2 receptor.

ACS Chem Neurosci 2010 Dec 23;1(12):788-95. Epub 2010 Aug 23.

Neuroscience Medicinal Chemistry, Johnson & Johnson Pharmaceutical Research & Development, Janssen-Cilag S.A., Calle Jarama 75, Polígono Industrial, Toledo 45007, Spain.

A series of 1,5-disubstituted pyridones was identified as positive allosteric modulators (PAMs) of the metabotropic glutamate receptor 2 (mGluR2) via high throughput screening (HTS). Subsequent SAR exploration led to the identification of several compounds with improved in vitro activity. Lead compound 8 was further profiled and found to attenuate the increase in PCP induced locomotor activity in mice.
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http://dx.doi.org/10.1021/cn1000638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3368638PMC
December 2010

Preclinical evaluation of 18F-JNJ41510417 as a radioligand for PET imaging of phosphodiesterase-10A in the brain.

J Nucl Med 2010 Oct 16;51(10):1584-91. Epub 2010 Sep 16.

Laboratory for Radiopharmacy, Faculty of Pharmaceutical Sciences, K.U. Leuven, Leuven, Belgium.

Unlabelled: Phosphodiesterases are enzymes that inactivate the intracellular second messengers 3',5'-cyclic adenosine-monophosphate and/or cyclic guanosine-monophosphate. Of all 11 known phosphodiesterase families, phosphodiesterase-10A (PDE10A) has the most restricted distribution, with high expression in the striatum. PDE10A inhibitors are pursued as drugs for treatment of neuropsychiatric disorders. We have synthesized and evaluated (18)F-JNJ41510417 as a selective and high-affinity radioligand for in vivo brain imaging of PDE10A using PET.

Methods: The biodistribution of (18)F-JNJ41510417 was evaluated in rats. Rat plasma and perfused brain homogenates were analyzed by high-performance liquid chromatography to quantify radiometabolites. Dynamic small-animal PET was performed in rats and in wild-type and PDE10A knock-out mice and compared with ex vivo autoradiography. Blocking and displacement experiments were performed using the nonradioactive analog and other selective PDE10A inhibitors.

Results: Tissue distribution studies showed predominant hepatobiliary excretion, sufficient brain uptake (0.56 ± 0.00 percentage injected dose at 2 min after tracer injection), and continuous accumulation of the tracer in the striatum over time; rapid washout of nonspecific binding from other brain regions was observed. Polar radiometabolites were detected in plasma and brain tissue. Dynamic small-animal PET showed continuous tracer accumulation in the striatum, with rapid decline in the cortex and cerebellum. Pretreatment and chase experiments with PDE10A inhibitors showed that the tracer binding to PDE10A was specific and reversible. Imaging in PDE10A knock-out and wild-type mice further confirmed that binding in the striatum was specific for PDE10A.

Conclusion: Experiments in rats and PDE10A knock-out mice indicate that (18)F-JNJ41510417 binds specifically and reversibly to PDE10A in the striatum, suggesting that this new fluorinated quinoline derivative is a promising candidate for in vivo imaging of PDE10A using PET.
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http://dx.doi.org/10.2967/jnumed.110.077040DOI Listing
October 2010

Novel approach for chemotype hopping based on annotated databases of chemically feasible fragments and a prospective case study: new melanin concentrating hormone antagonists.

J Med Chem 2009 Apr;52(7):2076-89

Department of Molecular Informatics, Johnson & Johnson Pharmaceutical R&D, Toledo, Spain.

A novel strategy for chemotype hopping, based on annotated databases of chemically feasible fragments and their oriented functionalization, is presented. A three-dimensional (3D) similarity analysis of project-oriented functionalized scaffolds provides a prioritized proposal for synthesis with the most appropriate linkers and optimal regiochemistry on R-groups. This strategy maximizes the potential of proprietary and commercially available compounds. A retrospective and prospective case study, on melanin concentrating hormone (MCH) antagonists, showing the impact on the drug discovery process of this new strategy by maintaining primary activity and improving key ADME/Tox property while enhancing intellectual property (IP) position is demonstrated.
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http://dx.doi.org/10.1021/jm8016199DOI Listing
April 2009

Synthesis of 2-N,N-dimethylaminomethyl-2,3,3a,12b-tetrahydrodibenzo-[b,f]furo[2,3-d]oxepin derivatives as potential anxiolytic agents.

Chem Pharm Bull (Tokyo) 2004 Feb;52(2):262-5

Johnson & Johnson Pharmaceutical Research & Development, a Division of Janssen-Cilag SA, Toledo, Spain.

New synthesis approaches that have led to a series of novel tetrahydrodibenzo[b,f]furo[2,3-d]oxepin derivatives are described. According to preliminary data these novel tetracycles can be useful intermediates for the preparation of potential new therapeutic agents.
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http://dx.doi.org/10.1248/cpb.52.262DOI Listing
February 2004