Publications by authors named "Ann J Barbier"

34 Publications

Safety and Efficacy of Mitapivat in Pyruvate Kinase Deficiency.

N Engl J Med 2019 09;381(10):933-944

From the Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston (R.F.G.), and Agios Pharmaceuticals, Cambridge (A.J.B., S.B., L.H., C.K., P.H., M.-H.J., C.B.) - all in Massachusetts; Hôpital Saint Vincent de Paul, Lille (C.R.), and Unité des Maladies Génétiques du Globule Rouge, Centre Hospitalier Universitaire Henri Mondor, Créteil (F.G.) - both in France; Hammersmith Hospital, Imperial College Healthcare NHS Trust, London (D.M.L.); Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan (W.B.); Central Pennsylvania Clinic, Belleville (D.H.M.), and Children's Hospital of Philadelphia and Perelman School of Medicine of the University of Pennsylvania, Philadelphia (J.L.K.); Van Creveldkliniek, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands (E.J.B.); University of Utah, Salt Lake City (H.Y.); Wayne State University School of Medicine, Children's Hospital of Michigan, Detroit (Y.R.); University of Toronto, Toronto (K.H.M.K.); Weill Cornell Medical College, New York (S.S.); Bruce A. Silver Clinical Science and Development, Dunkirk, MD (B.S.); and Stanford University School of Medicine, Palo Alto, CA (B.G.).

Background: Pyruvate kinase deficiency is caused by mutations in and leads to congenital hemolytic anemia. Mitapivat is an oral, small-molecule allosteric activator of pyruvate kinase in red cells.

Methods: In this uncontrolled, phase 2 study, we evaluated the safety and efficacy of mitapivat in 52 adults with pyruvate kinase deficiency who were not receiving red-cell transfusions. The patients were randomly assigned to receive either 50 mg or 300 mg of mitapivat twice daily for a 24-week core period; eligible patients could continue treatment in an ongoing extension phase.

Results: Common adverse events, including headache and insomnia, occurred at the time of drug initiation and were transient; 92% of the episodes of headache and 47% of the episodes of insomnia resolved within 7 days. The most common serious adverse events, hemolytic anemia and pharyngitis, each occurred in 2 patients (4%). A total of 26 patients (50%) had an increase of more than 1.0 g per deciliter in the hemoglobin level. Among these patients, the mean maximum increase was 3.4 g per deciliter (range, 1.1 to 5.8), and the median time until the first increase of more than 1.0 g per deciliter was 10 days (range, 7 to 187); 20 patients (77%) had an increase of more than 1.0 g per deciliter in the hemoglobin level at more than 50% of visits during the core study period, with improvement in markers of hemolysis. The response was sustained in all 19 patients remaining in the extension phase, with a median follow-up of 29 months (range, 22 to 35). Hemoglobin responses were observed only in patients who had at least one missense mutation and were associated with the red-cell pyruvate kinase protein level at baseline.

Conclusions: The administration of mitapivat was associated with a rapid increase in the hemoglobin level in 50% of adults with pyruvate kinase deficiency, with a sustained response during a median follow-up of 29 months during the extension phase. Adverse effects were mainly low-grade and transient. (Funded by Agios Pharmaceuticals; ClinicalTrials.gov number, NCT02476916.).
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http://dx.doi.org/10.1056/NEJMoa1902678DOI Listing
September 2019

Phase 1 Single- and Multiple-Ascending-Dose Randomized Studies of the Safety, Pharmacokinetics, and Pharmacodynamics of AG-348, a First-in-Class Allosteric Activator of Pyruvate Kinase R, in Healthy Volunteers.

Clin Pharmacol Drug Dev 2019 02 9;8(2):246-259. Epub 2018 Aug 9.

Agios Pharmaceuticals, Inc., Cambridge, MA, USA.

Pyruvate kinase deficiency is a chronic hemolytic anemia caused by mutations in PK-R, a key glycolytic enzyme in erythrocytes. These 2 phase 1 randomized, placebo-controlled, double-blind healthy-volunteer studies assessed the safety, tolerability, and pharmacokinetics/pharmacodynamics of AG-348, a first-in-class allosteric PK-R activator. Twelve sequential cohorts were randomized 2:6 to receive oral placebo or AG-348, respectively, as a single dose (30-2500 mg) in the single-ascending-dose (SAD) study (ClinicalTrials.gov: NCT02108106) or 15-700 mg every 12 hours or 120 mg every 24 hours, for 14 days in the multiple-ascending-dose (MAD) study (ClinicalTrials.gov: NCT02149966). All 48 subjects completed the fasted SAD part; 44 of 48 completed the MAD (2 discontinued because of adverse events [AEs], 2 withdrew consent). The most common treatment-related AEs in AG-348-treated subjects were headache (16.7% [SAD] and 13.9% [MAD]) and nausea (13.9%, both studies). AE frequency increased at AG-348 doses ≥ 700 mg (SAD) and at 700 mg every 12 hours (MAD); 1 grade ≥ 3 AE occurred in the latter cohort. Pharmacokinetics were favorable with low variability. Dose-dependent changes in blood glycolytic intermediates consistent with glycolytic pathway activation were observed at all MAD doses, supporting future trials investigating the potential of AG-348 for treating PK deficiency or other anemias.
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http://dx.doi.org/10.1002/cpdd.604DOI Listing
February 2019

Patient Voice in Rare Disease Drug Development and Endpoints.

Ther Innov Regul Sci 2017 Mar 4;51(2):257-263. Epub 2016 Nov 4.

6 Stealth BioTherapeutics, Newton, MA, USA.

While planning for a successful clinical trial in a prevalent condition is no trivial orchestration, even more complicated is the coordination of novel, delicate and critical operational components necessary for the successful conduct of clinical trials of rare disease (RD). We highlight some of the inherent and practical challenges to conducting clinical trials and selecting or developing endpoints for RD and the importance of including the patient voice or perspective. These challenges include the lack of regulatory precedent for proposed endpoints, a void of available measures, little or no published literature or natural history information, the practicalities of obtaining access to patients, and the appropriateness of placebo-controlled trials. As part of our review, we include practical considerations for addressing these issues along with a regulatory perspective regarding potential logistic and methodologic challenges. We conclude that the patient perspective is a critical component in defining treatment benefit and in interpreting the meaningfulness of a change (or lack thereof). Engaging with patients is needed at multiple steps along the long road of drug discovery.
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http://dx.doi.org/10.1177/2168479016671559DOI Listing
March 2017

A phase 1/2 study of intrathecal heparan-N-sulfatase in patients with mucopolysaccharidosis IIIA.

Mol Genet Metab 2016 07 10;118(3):198-205. Epub 2016 May 10.

Department of Paediatrics, Academic Medical Center, Amsterdam, The Netherlands. Electronic address:

Objective: This was an open-label, phase 1/2 dose-escalation, safety trial of intrathecal recombinant human heparan-N-sulfatase (rhHNS) administered via intrathecal drug delivery device (IDDD) for treating mucopolysaccharidosis IIIA (NCT01155778).

Study Design: Twelve patients received 10, 45, or 90mg of rhHNS via IDDD once monthly for a total of 6 doses. Primary endpoints included adverse events (AEs) and anti-rhHNS antibodies. Secondary endpoints included standardized neurocognitive assessments, cortical gray matter volume, and pharmacokinetic/pharmacodynamic analyses.

Results: All patients experienced treatment-emergent AEs; most of mild-to-moderate severity. Seven patients reported a total of 10 serious AEs (SAEs), all but one due to hospitalization to revise a nonfunctioning IDDD. No SAEs were considered related to rhHNS. Anti-rhHNS antibodies were detected in the serum of 6 patients and in the cerebrospinal fluid (CSF) of 2 of these. CSF heparan sulfate levels were elevated at baseline and there were sustained declines in all tested patients following the first rhHNS dose. No impact of anti-rhHNS antibodies on any pharmacodynamic or safety parameters was evident. 4 of 12 patients showed a decline in developmental quotient, 6 were stable, and 2 patients had only a single data point. No dose group showed a clearly different response pattern.

Conclusions: rhHNS administration via IDDD appeared generally safe and well tolerated. Treatment resulted in consistent declines in CSF heparan sulfate, suggesting in vivo activity in the relevant anatomical compartment. Results of this small study should be interpreted with caution. Future studies are required to assess the potential clinical benefits of rhHNS and to test improved IDDD models.
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http://dx.doi.org/10.1016/j.ymgme.2016.05.006DOI Listing
July 2016

Neurocognitive clinical outcome assessments for inborn errors of metabolism and other rare conditions.

Mol Genet Metab 2016 06 14;118(2):65-9. Epub 2016 Apr 14.

Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA. Electronic address:

Well-defined and reliable clinical outcome assessments are essential for determining whether a drug provides clinically meaningful treatment benefit for patients. In 2015, FDA convened a workshop, "Assessing Neurocognitive Outcomes in Inborn Errors of Metabolism." Topics covered included special challenges of clinical studies of inborn errors of metabolism (IEMs) and other rare diseases; complexities of identifying treatment effects in the context of the dynamic processes of child development and disease progression; and the importance of natural history studies. Clinicians, parents/caregivers, and participants from industry, academia, and government discussed factors to consider when developing measures to assess treatment outcomes, as well as tools and methods that may contribute to standardizing measures. Many issues examined are relevant to the broader field of rare diseases in addition to specifics of IEMs.
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http://dx.doi.org/10.1016/j.ymgme.2016.04.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4895194PMC
June 2016

A novel LC-MS/MS assay for heparan sulfate screening in the cerebrospinal fluid of mucopolysaccharidosis IIIA patients.

Bioanalysis 2016 Feb 5;8(4):285-95. Epub 2016 Feb 5.

Shire, 300 Shire Way, Lexington, MA 02421, USA.

Aims: Heparan sulfate (HS) accumulates in the central nervous system in mucopolysaccharidosis III type A (MPS IIIA). A validated LC-MS/MS assay was developed to measure HS in human cerebrospinal fluid (CSF).

Methods & Results: HS was extracted and digested and the resultant disaccharides were derivatized with a novel label, 4-butylaniline, enabling isoform separation and isotope-tagged analog introduction as an internal standard for LC-MS/MS. The assay has a LLOQ for disaccharides of 0.1 μM, ±20% accuracy and ≤20% precision. CSF samples from patients with MPS IIIA showed elevated HS levels (mean 4.9 μM) compared with negative controls (0.37 μM).

Conclusion: This assay detected elevated HS levels in the CSF of patients with MPS IIIA and provides a method to assess experimental therapies.
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http://dx.doi.org/10.4155/bio.15.243DOI Listing
February 2016

Levels of glycosaminoglycans in the cerebrospinal fluid of healthy young adults, surrogate-normal children, and Hunter syndrome patients with and without cognitive impairment.

Mol Genet Metab Rep 2015 Dec 9;5:103-106. Epub 2015 Nov 9.

Shire, 300 Shire Way, Lexington, MA 02421, USA.

In mucopolysaccharidoses (MPS), glycosaminoglycans (GAG) accumulate in tissues. In MPS II, approximately two-thirds of patients are cognitively impaired. We investigated levels of GAG in cerebrospinal fluid (CSF) in different populations from four clinical studies (including NCT00920647 and NCT01449240). Data indicate that MPS II patients with cognitive impairment have elevated levels of CSF GAG, whereas those with the attenuated phenotype typically have levels falling between those of the cognitively affected patients and healthy controls.
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http://dx.doi.org/10.1016/j.ymgmr.2015.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5471392PMC
December 2015

Immunogenicity of idursulfase and clinical outcomes in very young patients (16 months to 7.5 years) with mucopolysaccharidosis II (Hunter syndrome).

Orphanet J Rare Dis 2015 Apr 24;10:50. Epub 2015 Apr 24.

Shire, 300 Shire Way, Lexington, MA, 02421, USA.

Background: Twenty-eight treatment-naïve mucopolysaccharidosis II patients (16 months-7.5 years) received 0.5 mg/kg idursulfase weekly for one year in NCT00607386. Serum anti-idursulfase immunoglobulin G antibodies (Abs) were seen in 68% of patients.

Methods: This post hoc analysis examined the relationship between Ab status, genotype, adverse events (AEs), and efficacy. Event rate analyses, time-varying proportional hazards (Cox) modeling, and landmark analyses were performed to evaluate the relationship between Ab status and safety. We calculated the cumulative probability of AEs by genotype to evaluate the relationship between genotype and safety. Urinary glycosaminoglycan (uGAG) concentration, index of liver size, and spleen volume were compared by Ab status and genotype.

Safety Results: The overall infusion-related AE (IRAE) rate was higher in Ab+ patients than in Ab- ones. However, the rate was highest before Abs developed, then decreased over time, suggesting that Abs did not confer the risk. A landmark analysis of patients who were IRAE-naïve at the landmark point found that Ab+ patients were no more likely to experience post-landmark IRAEs than were Ab- patients. In the genotype analysis, all patients in the complete deletion/large rearrangement (CD/LR) and frame shift/splice site mutation (FS/SSM) groups seroconverted, compared with only one-third of patients in the missense mutation (MS) group (p < 0.001). The cumulative probability of having ≥1 IRAE was 87.5% in the CD/LR group and 46.2% in the MS group, with a shorter time to first IRAE in the CD/LR group (p = 0.004).

Efficacy Results: Ab+ patients had a reduced response to idursulfase for liver size and uGAG concentration, but not for spleen size. However, when percent change from baseline in liver size and in uGAG level at Week 53 were adjusted for genotype, the difference was significant only for neutralizing Ab+ groups. In the genotype analysis, the CD/LR and FS/SSM groups had a reduced response in liver size and uGAG concentration compared with the MS group.

Conclusions: Safety outcomes and spleen size response on idursulfase treatment appeared to be associated with genotype, not Ab status. Liver size and uGAG response on idursulfase treatment at Week 53 appeared to be associated with both neutralizing Ab status and genotype.
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http://dx.doi.org/10.1186/s13023-015-0265-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4416269PMC
April 2015

Novel benzamide-based histamine h3 receptor antagonists: the identification of two candidates for clinical development.

ACS Med Chem Lett 2015 Apr 13;6(4):450-4. Epub 2015 Mar 13.

Janssen Pharmaceutical Company, a division of Johnson & Johnson Pharmaceutical Research & Development L.L.C. , 3210 Merryfield Row, San Diego, California 92121, United States.

The preclinical characterization of novel phenyl(piperazin-1-yl)methanones that are histamine H3 receptor antagonists is described. The compounds described are high affinity histamine H3 antagonists. Optimization of the physical properties of these histamine H3 antagonists led to the discovery of several promising lead compounds, and extensive preclinical profiling aided in the identification of compounds with optimal duration of action for wake promoting activity. This led to the discovery of two development candidates for Phase I and Phase II clinical trials.
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http://dx.doi.org/10.1021/ml5005156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4394347PMC
April 2015

A phase I/II study of intrathecal idursulfase-IT in children with severe mucopolysaccharidosis II.

Genet Med 2016 Jan 2;18(1):73-81. Epub 2015 Apr 2.

Shire, Lexington, Massachusetts, USA.

Purpose: Approximately two-thirds of patients with the lysosomal storage disease mucopolysaccharidosis II have progressive cognitive impairment. Intravenous (i.v.) enzyme replacement therapy does not affect cognitive impairment because recombinant iduronate-2-sulfatase (idursulfase) does not penetrate the blood-brain barrier at therapeutic concentrations. We examined the safety of idursulfase formulated for intrathecal administration (idursulfase-IT) via intrathecal drug delivery device (IDDD). A secondary endpoint was change in concentration of glycosaminoglycans in cerebrospinal fluid.

Methods: Sixteen cognitively impaired males with mucopolysaccharidosis II who were previously treated with weekly i.v. idursulfase 0.5 mg/kg for ≥6 months were enrolled. Patients were randomized to no treatment or 10-mg, 30-mg, or 1-mg idursulfase-IT monthly for 6 months (four patients per group) while continuing i.v. idursulfase weekly.

Results: No serious adverse events related to idursulfase-IT were observed. Surgical revision/removal of the IDDD was required in 6 of 12 patients. Twelve total doses were administrated by lumbar puncture. Mean cerebrospinal fluid glycosaminoglycan concentration was reduced by approximately 90% in the 10-mg and 30-mg groups and approximately 80% in the 1-mg group after 6 months.

Conclusions: These preliminary data support further development of investigational idursulfase-IT in MPS II patients with the severe phenotype who have progressed only to a mild-to-moderate level of cognitive impairment.Genet Med 18 1, 73-81.
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http://dx.doi.org/10.1038/gim.2015.36DOI Listing
January 2016

Pharmacodynamics, pharmacokinetics, safety, and tolerability of encenicline, a selective α7 nicotinic receptor partial agonist, in single ascending-dose and bioavailability studies.

Clin Ther 2015 Feb 14;37(2):311-24. Epub 2014 Oct 14.

Forum Pharmaceuticals, Boston, Massachusetts. Electronic address:

Purpose: Encenicline (EVP-6124) is a selective α7 nicotinic acetylcholine receptor partial agonist being developed for cognitive impairment in Alzheimer's disease and schizophrenia. We report on 2 single-dose studies to assess the relative bioavailability, pharmacokinetic profile, tolerability, and cognitive effects of encenicline in healthy volunteers.

Methods: A single ascending-dose study assessed the safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of encenicline in healthy male volunteers. Subjects received a single 1-, 3.5-, 7-, 20-, 60-, or 180-mg oral solution dose of encenicline or placebo. A second single-dose, randomized, open-label, 3-period, crossover study in healthy male and female subjects compared the relative bioavailability of a 1-mg oral capsule versus a 1-mg oral solution dose of encenicline and evaluated the effects of food and sex on encenicline pharmacokinetic profile.

Findings: In the first study, encenicline was well tolerated and dose-proportional increases in C(max) (mean range 0.59-100 ng/mL) and AUC0-∞ (mean range 45.6-8890 ng·h/mL) were observed over a 1- to 180-mg dose range. Procognitive effects on the Digit Symbol Substitution Test were maximal at the 20-mg dose. In the second study, encenicline 1-mg oral capsules and oral solution were bioequivalent and there was no observed food effect on encenicline pharmacokinetic profile with the 90% confidence intervals of the treatment ratios for both comparisons (ie, capsule to solution and fed to fasted) for Cmax and AUC being within 80% to 125%. A 30% to 40% higher encenicline exposure in female subjects than respective values in male subjects was consistent with a 33% higher weight of the male subjects. No clinically relevant safety profile or tolerability effects of encenicline were observed.

Implications: Encenicline was well tolerated at single doses up to 180 mg, and doses as low as 1 mg had dose- and time-dependent pharmacodynamic effects on the central nervous system. Oral capsule and solution were bioequivalent and were not affected by food. Although a sex effect on pharmacokinetic profile was observed, it was attributable to weight differences. Clinical Trial Registration at EudraCT: 2006-005623-42 and EudracT: 2008-000029-20.
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http://dx.doi.org/10.1016/j.clinthera.2014.09.013DOI Listing
February 2015

Heterocyclic replacement of the central phenyl core of diamine-based histamine H3 receptor antagonists.

Eur J Med Chem 2009 Nov 16;44(11):4413-25. Epub 2009 Jun 16.

Johnson & Johnson Pharmaceutical Research and Development, LLC, San Diego, CA 92121, United States.

A series of small molecules consisting of a heterocyclic core flanked by two basic functionalities were synthesized and screened for in vitro affinity at the human histamine H(3) receptor (hH(3)R). Nine of the twenty-eight compounds tested were found to possess a hH(3)R K(i) of less than 5 nM and consisted of a diverse range of central hetero-aromatic linkers (pyridine, pyrazine, oxazole, isoxazole, thiazole, furan, thiophene, and pyrrole). One member of this series, (4-isopropyl-piperazin-1-yl)-(6-piperidin-1-ylmethyl-pyridin-3-yl)-methanone (37), was found to be a high affinity, selective antagonist that crosses the blood-brain barrier and occupies H(3) receptors after oral administration in the rat.
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http://dx.doi.org/10.1016/j.ejmech.2009.06.007DOI Listing
November 2009

In-vitro and in-vivo characterization of JNJ-7925476, a novel triple monoamine uptake inhibitor.

Eur J Pharmacol 2008 Jun 10;587(1-3):141-6. Epub 2008 Apr 10.

Department of Neuroscience, Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.

Triple reuptake inhibitors, which block the serotonin transporter (SERT), norepinephrine transporter (NET) and dopamine transporter (DAT) in the central nervous system have been described as therapeutic alternatives for classical selective serotonin reuptake inhibitors, with advantages due to their multiple mechanisms of action. JNJ-7925476 (trans-6-(4-ethynylphenyl)-1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinoline) is a selective and potent inhibitor of the SERT, NET, and DAT (K(i)=0.9, 17 and 5.2 nM, respectively). Following subcutaneous dosing in rat, JNJ-7925476 was rapidly absorbed into the plasma, and drug concentrations in the brain tracked with those in the plasma but were 7-fold higher. The ED(50) values for JNJ-7925476 occupancy of the SERT, NET, and DAT in rat brain were 0.18, 0.09 and 2.4 mg/kg, respectively. JNJ-7925476 (0.1-10 mg/kg, s.c.) rapidly induced a robust, dose-dependent increase in extracellular serotonin, dopamine, and norepinephrine levels in rat cerebral cortex. The compound also showed potent antidepressant-like activity in the mouse tail suspension test (ED(50)=0.3 mg/kg, i.p.). These results demonstrate that JNJ-7925476 is a triple reuptake inhibitor with in-vivo efficacy in biochemical and behavioral models of depression.
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http://dx.doi.org/10.1016/j.ejphar.2008.04.008DOI Listing
June 2008

Lead identification of acetylcholinesterase inhibitors-histamine H3 receptor antagonists from molecular modeling.

Bioorg Med Chem 2008 Mar 25;16(6):2968-73. Epub 2007 Dec 25.

Johnson & Johnson Pharmaceutical Research and Development, L.L.C. 3210 Merryfield Row, San Diego, CA 92121, USA.

Currently, the only clinically effective treatment for Alzheimer's disease (AD) is the use of acetylcholinesterase (AChE) inhibitors. These inhibitors have limited efficacy in that they only treat the symptoms and not the disease itself. Additionally, they often have unpleasant side effects. Here we consider the viability of a single molecule having the actions of both an AChE inhibitor and histamine H(3) receptor antagonist. Both histamine H(3) receptor antagonists and AChE inhibitors improve and augment cholinergic neurotransmission in the cortex. However, whereas an AChE inhibitor will impart its effect everywhere, a histamine H(3) antagonist will raise acetylcholine levels mostly in the brain as its mode of action will primarily be on the central nervous system. Therefore, the combination of both activities in a single molecule could be advantageous. Indeed, studies suggest an appropriate dual-acting compound may offer the desired therapeutic effect with fewer unpleasant side effects [CNS Drugs2004, 18, 827]. Further, recent studies(2) indicate the peripheral anionic site (PAS) of AChE interacts with the beta-amyloid (betaA) peptide. Consequently, a molecule capable of disrupting this interaction may have a significant impact on the production of or the aggregation of betaA. This may result in slowing down the progression of the disease rather than only treating the symptoms as current therapies do. Here, we detail how the use of the available crystal structure information, pharmacophore modeling and docking (automated, manual, classical, and QM/MM) lead to the identification of an AChE inhibitor-histamine H(3) receptor antagonist. Further, based on our models we speculate that this dual-acting compound may interact with the PAS. Such a dual-acting compound may be able to affect the pathology of AD in addition to providing symptomatic relief.
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http://dx.doi.org/10.1016/j.bmc.2007.12.048DOI Listing
March 2008

Synthesis and biological activity of piperazine and diazepane amides that are histamine H3 antagonists and serotonin reuptake inhibitors.

Bioorg Med Chem Lett 2008 Jan 13;18(1):39-43. Epub 2007 Nov 13.

Johnson & Johnson Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.

The synthesis and biological activity of a new series of piperazine and diazepane amides is described. The new compounds are high affinity histamine H3 ligands and serotonin reuptake inhibitors.
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http://dx.doi.org/10.1016/j.bmcl.2007.11.016DOI Listing
January 2008

Dual serotonin transporter inhibitor/histamine H3 antagonists: development of rigidified H3 pharmacophores.

Bioorg Med Chem Lett 2007 Oct 15;17(19):5325-9. Epub 2007 Aug 15.

Johnson & Johnson Pharmaceutical Research and Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.

A series of tetrahydroisoquinolines acting as dual serotonin transporter inhibitor/histamine H(3) antagonists is described. The introduction of polar aromatic spacers as part of the histamine H(3) pharmacophore was explored. A convergent synthesis of the final products allowing late stage introduction of the aromatic side chain was developed. In vitro and in vivo data are discussed.
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http://dx.doi.org/10.1016/j.bmcl.2007.08.017DOI Listing
October 2007

Pharmacological characterization of JNJ-28583867, a histamine H(3) receptor antagonist and serotonin reuptake inhibitor.

Eur J Pharmacol 2007 Dec 14;576(1-3):43-54. Epub 2007 Aug 14.

Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.

Wake-promoting agents such as modafinil are used in the clinic as adjuncts to antidepressant therapy in order to alleviate lethargy. The wake-promoting action of histamine H(3) receptor antagonists has been evidenced in numerous animal studies. They may therefore be a viable strategy for use as an antidepressant therapy in conjunction with selective serotonin reuptake inhibitors. JNJ-28583867 (2-Methyl-4-(4-methylsulfanyl-phenyl)-7-(3-morpholin-4-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline) is a selective and potent histamine H(3) receptor antagonist (K(i)=10.6 nM) and inhibitor of the serotonin transporter (SERT) (K(i)=3.7 nM), with 30-fold selectivity for SERT over the dopamine and norepinephrine transporters. After subcutaneous administration, JNJ-28583867 occupied both the histamine H(3) receptor and the SERT in rat brain at low doses (<1 mg/kg). JNJ-28583867 blocked imetit-induced drinking (3-10 mg/kg i.p.), confirming in vivo functional activity at the histamine H(3) receptor and also significantly increased cortical extracellular levels of serotonin at doses of 0.3 mg/kg (s.c.) and higher. Smaller increases in cortical extracellular levels of norepinephrine and dopamine were also observed. JNJ-28583867 (3-30 mg/kg p.o.) showed antidepressant-like activity in the mouse tail suspension test. JNJ-28583867 (1-3 mg/kg s.c.) caused a dose-dependent increase in the time spent awake mirrored by a decrease in NREM. Concomitantly, JNJ-28583867 produced a potent suppression of REM sleep from the dose of 1 mg/kg onwards. JNJ-28583867 has good oral bioavailability in the rat (32%), a half-life of 6.9 h and a C(max) of 260 ng/ml after 10 mg/kg p.o. In summary, JNJ-28583867 is a combined histamine H(3) receptor antagonist-SERT inhibitor with in vivo efficacy in biochemical and behavioral models of depression and wakefulness.
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http://dx.doi.org/10.1016/j.ejphar.2007.08.009DOI Listing
December 2007

Benzylamine histamine H(3) antagonists and serotonin reuptake inhibitors.

Bioorg Med Chem Lett 2007 Sep 26;17(17):4799-803. Epub 2007 Jun 26.

Johnson & Johnson Pharmaceutical Research & Development LLC, 3210 Merryfield Row, San Diego, CA 92121, USA.

The design, synthesis, and in vitro activity of a series of novel 5-ethynyl-2-aryloxybenzylamine-based histamine H(3) ligands that are also serotonin reuptake transporters is described.
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http://dx.doi.org/10.1016/j.bmcl.2007.06.061DOI Listing
September 2007

Pyrrolidino-tetrahydroisoquinolines bearing pendant heterocycles as potent dual H3 antagonist and serotonin transporter inhibitors.

Bioorg Med Chem Lett 2007 Aug 16;17(15):4374-7. Epub 2007 Mar 16.

Johnson & Johnson Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, La Jolla, CA 92121, USA.

A series of novel and potent 6-heteroaryl-pyrrolidino-tetrahydroisoquinolines with dual histamine H(3) antagonist/serotonin transporter inhibitor activity is described. In vitro and in vivo data are discussed.
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http://dx.doi.org/10.1016/j.bmcl.2007.03.043DOI Listing
August 2007

Synthesis and biological evaluation of diamine-based histamine H3 antagonists with serotonin reuptake inhibitor activity.

Bioorg Med Chem Lett 2007 Jun 15;17(11):3130-5. Epub 2007 Mar 15.

Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.

The synthesis and structure-activity relationships of a series of novel phenoxyphenyl diamine derivatives with affinity for both the histamine H(3) receptor and the serotonin transporter is described.
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http://dx.doi.org/10.1016/j.bmcl.2007.03.034DOI Listing
June 2007

Pyrrolidino-tetrahydroisoquinolines as potent dual H3 antagonist and serotonin transporter inhibitors.

Bioorg Med Chem Lett 2007 May 4;17(9):2603-7. Epub 2007 Feb 4.

Johnson & Johnson Pharmaceutical Research and Development L.L.C., 3210 Merryfield Row, La Jolla, CA 92121, USA.

A series of novel and potent pyrrolidino-tetrahydroisoquinolines with dual histamine H(3) antagonist/serotonin transporter inhibitor activity is described. A highly regio- and diastereoselective synthesis of the pyrrolidino-tetrahydroisoquinoline core involving acid mediated ring-closure of an acetophenone intermediate followed by reduction with NaCNBH(3) was developed. In vitro and in vivo data are discussed.
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http://dx.doi.org/10.1016/j.bmcl.2007.01.106DOI Listing
May 2007

Novel naphthyridines are histamine H3 antagonists and serotonin reuptake transporter inhibitors.

Bioorg Med Chem Lett 2007 May 4;17(9):2566-9. Epub 2007 Feb 4.

Johnson & Johnson Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121-1126, USA.

A series of novel tetrahydronaphthyridine-based histamine H(3) ligands that have serotonin reuptake transporter inhibitor activity is described. The 1,2,3,4-tetrahydro-2,6-naphthyridine scaffold is assembled via the addition of a nitrostyrene to a metalated pyridine followed by reduction and cyclization to form the naphthyridine. In vitro biological data for these novel compounds are discussed.
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http://dx.doi.org/10.1016/j.bmcl.2007.02.006DOI Listing
May 2007

Novel tetrahydroisoquinolines are histamine H3 antagonists and serotonin reuptake inhibitors.

Bioorg Med Chem Lett 2007 Feb 16;17(4):1047-51. Epub 2006 Nov 16.

Johnson & Johnson Pharmaceutical Research and Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.

A series of novel 4-aryl-1,2,3,4-tetrahydroisoquinoline-based histamine H(3) ligands that also have serotonin reuptake transporter inhibitor activity is described. The synthesis, in vitro biological data, and select pharmacokinetic data for these novel compounds are discussed.
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http://dx.doi.org/10.1016/j.bmcl.2006.11.036DOI Listing
February 2007

Dual serotonin transporter/histamine H3 ligands: Optimization of the H3 pharmacophore.

Bioorg Med Chem Lett 2007 Feb 2;17(3):702-6. Epub 2006 Nov 2.

Johnson & Johnson Pharmaceutical Research and Development LLC, 3210 Merryfield Row, San Diego, CA 92121, USA.

A series of tetrahydroisoquinolines acting as dual histamine H3/serotonin transporter ligands is described. A highly regio-selective synthesis of the tetrahydroisoquinoline core involving acid mediated ring-closure of an acetophenone intermediate followed by reduction with NaCNBH3 was developed. In vitro and in vivo data are discussed.
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http://dx.doi.org/10.1016/j.bmcl.2006.10.089DOI Listing
February 2007

Radiosynthesis and biodistribution of a histamine H3 receptor antagonist 4-[3-(4-piperidin-1-yl-but-1-ynyl)-[11C]benzyl]-morpholine: evaluation of a potential PET ligand.

Nucl Med Biol 2006 Aug;33(6):801-10

Department of Nuclear Medicine and PET Research, Location Radionuclide Center, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands.

The potent histamine H(3) receptor antagonist JNJ-10181457 (1) was successfully labeled with (11)C in a novel one-pot reaction sequence, with high chemical yield (decay-corrected yield, 28+/-8%) and high specific radioactivity (56+/-26 GBq/mumol). The binding of [(11)C]1 to H(3) receptors was studied in vitro in rat brain and in vivo in rats and mice. The in vitro binding of [(11)C]1 in rat coronal brain slices showed high binding in the striatum, and this binding was blocked by histamine and by two known H(3) antagonists, JNJ-5207852 (2) and unlabeled Compound (1), in a concentration-dependent manner. The biodistribution of [(11)C]1 in rats was measured at 5, 10, 30 and 60 min. The uptake of [(11)C]1 in regions rich in H(3) receptors was highest at 30 min, giving 0.98%, 1.41%, 1.28% and 1.72% dose/g for the olfactory bulb, hippocampus, striatum and cerebral cortex, respectively. However, the binding of [(11)C]1 in the rat brain could not be blocked by pretreatment with either Compound (2) (30 min or 24 h pretreatment) or cold Compound (1) (30-min pretreatment). The biodistribution of [(11)C]1 in a second species (Balb/c mice) showed a higher overall uptake of the radioligand with an average brain uptake of 8.9% dose/g. In C57BL/6-H(3)(-/-) knockout mice, a higher brain uptake was also observed. Analyses of metabolites and plasma protein binding were also undertaken. It appeared that [(11)C]1 could not specifically label H(3) receptors in rodent brain in vivo. Possible causes are discussed.
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http://dx.doi.org/10.1016/j.nucmedbio.2006.05.008DOI Listing
August 2006

Recent medicinal chemistry of the histamine H3 receptor.

Prog Med Chem 2006 ;44:181-206

Johnson and Johnson Pharmaceutical Research and Development LLC, San Diego, CA 92121, USA.

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http://dx.doi.org/10.1016/S0079-6468(05)44405-7DOI Listing
November 2007

Inhibition of fatty acid amide hydrolase produces analgesia by multiple mechanisms.

Br J Pharmacol 2006 May;148(1):102-13

Johnson & Johnson Pharmaceutical Research & Development, L.L.C., San Diego, CA 92121-1126, USA.

1 The reversible fatty acid amide hydrolase (FAAH) inhibitor OL135 reverses mechanical allodynia in the spinal nerve ligation (SNL) and mild thermal injury (MTI) models in the rat. The purpose of this study was to investigate the role of the cannabinoid and opioid systems in mediating this analgesic effect. 2 Elevated brain concentrations of anandamide (350 pmol g(-1) of tissue vs 60 pmol g(-1) in vehicle-treated controls) were found in brains of rats given OL135 (20 mg kg(-1)) i.p. 15 min prior to 20 mg kg(-1) i.p. anandamide. 3 Predosing rats with OL135 (2-60 mg kg(-1) i.p.) 30 min before administration of an irreversible FAAH inhibitor (URB597: 0.3 mg kg(-1) intracardiac) was found to protect brain FAAH from irreversible inactivation. The level of enzyme protection was correlated with the OL135 concentrations in the same brains. 4 OL135 (100 mg kg(-1) i.p.) reduced by 50% of the maximum possible efficacy (MPE) mechanical allodynia induced by MTI in FAAH(+/+)mice (von Frey filament measurement) 30 min after dosing, but was without effect in FAAH(-/-) mice. 5 OL135 given i.p. resulted in a dose-responsive reversal of mechanical allodynia in both MTI and SNL models in the rat with an ED(50) between 6 and 9 mg kg(-1). The plasma concentration at the ED(50) in both models was 0.7 microM (240 ng ml(-1)). 6 In the rat SNL model, coadministration of the selective CB(2) receptor antagonist SR144528 (5 mg kg(-1) i.p.), with 20 mg kg(-1) OL135 blocked the OL135-induced reversal of mechanical allodynia, but the selective CB(1) antagonist SR141716A (5 mg kg(-1) i.p.) was without effect. 7 In the rat MTI model neither SR141716A or SR144528 (both at 5 mg kg(-1) i.p.), or a combination of both antagonists coadministered with OL135 (20 mg kg(-1)) blocked reversal of mechanical allodynia assessed 30 min after dosing. 8 In both the MTI model and SNL models in rats, naloxone (1 mg kg(-1), i.p. 30 min after OL135) reversed the analgesia (to 15% of control levels in the MTI model, to zero in the SNL) produced by OL135.
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http://dx.doi.org/10.1038/sj.bjp.0706699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1617043PMC
May 2006

Aplysamine-1 and related analogs as histamine H3 receptor antagonists.

Bioorg Med Chem Lett 2006 Feb 21;16(4):897-900. Epub 2005 Nov 21.

Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.

Aplysamine-1 (1), a marine natural product, was synthesized and screened for in vitro activity at the human and rat histamine H3 receptors. Aplysamine-1 (1) was found to possess a high binding affinity for the human H3 receptor (Ki = 30+/-4 nM). Synthetic analogs of 1, including des-bromoaplysamine-1 (10) and dimethyl-{2-[4-(3-piperidin-1-yl-propoxy)-phenyl]-ethyl}-amine (13), were potent H3 antagonists.
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http://dx.doi.org/10.1016/j.bmcl.2005.11.003DOI Listing
February 2006

4-phenoxypiperidines: potent, conformationally restricted, non-imidazole histamine H3 antagonists.

J Med Chem 2005 Mar;48(6):2229-38

Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 3210 Merryfield Row, San Diego, California 92121, USA.

Two new series of 4-(1-alkyl-piperidin-4-yloxy)-benzonitriles and 4-(1-isopropyl-piperidin-4-yloxy)-benzylamines have been prepared. In vitro activity was determined at the recombinant human H(3) receptor and several members of these new series were found to be potent H(3) antagonists. The present compounds contain a 4-phenoxypiperidine core, which behaves as a conformationally restricted version of the 3-amino-1-propanol moiety common to the many previously described non-imidazole histamine H(3) ligands. One selected member of the new series, 4-[4-(1-isopropyl-piperidin-4-yloxy)-benzyl]-morpholine (13g), was found to be a potent, highly selective H(3) receptor antagonist with in vivo efficacy in a rat EEG model of wakefulness at doses as low as 1 mg/kg sc.
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http://dx.doi.org/10.1021/jm049212nDOI Listing
March 2005

A simple stopped assay for fatty acid amide hydrolase avoiding the use of a chloroform extraction phase.

J Biochem Biophys Methods 2004 Aug;60(2):171-7

Department of Pharmacology and Clinical Neuroscience, Umeå University, SE901 87 Umeå, Sweden.

A stopped assay for fatty acid amide hydrolase (FAAH) has been developed, whereby the enzyme reaction product ([(3)H]ethanolamine) was separated from substrate (anandamide [ethanolamine-1-(3)H]), by differential adsorption to charcoal. The assay gave a better extraction efficiency when acidic rather than alkaline charcoal solutions were used to stop the reaction, and a very good ratio of sample/blank was also seen. The acidic charcoal assay gave the expected sensitivities to compounds known to inhibit FAAH (palmitoyltrifluoromethyl ketone, arvanil, AM404 and indomethacin). It is concluded that the acidic charcoal extraction method provides a robust and simple stopped assay for FAAH without the need to use potentially hazardous solvents like chloroform.
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http://dx.doi.org/10.1016/j.jbbm.2004.04.020DOI Listing
August 2004