Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 14 de 14
Filter
1.
Ann Clin Transl Neurol ; 5(10): 1250-1263, 2018 Oct.
Article in English | MEDLINE | ID: mdl-30349860

ABSTRACT

OBJECTIVE: The prognostic value of cerebrospinal fluid neurofilament light chain, total tau, phosphorylated tau181, and amyloid beta1-42 was examined in frontotemporal dementia subtypes. METHODS: We compared baseline biomarkers between 49 controls, 40 patients with behavioral variant frontotemporal dementia, 24 with semantic variant primary progressive aphasia, and 26 with nonfluent variant primary progressive aphasia. Linear mixed effect models were used to assess the value of baseline biomarkers in predicting clinical and radiographic change in patient cohorts over multiple yearly follow up visits. RESULTS: Neurofilament light chain concentrations were lowest in controls. Elevated baseline neurofilament light chain predicted faster worsening in clinical severity, frontotemporal volume and frontotemporal fractional anisotropy in patients with behavioral variant frontotemporal dementia and nonfluent variant primary progressive aphasia. High total tau similarly predicted faster progression in nonfluent variant primary progressive aphasia. In behavioral variant frontotemporal dementia, higher phosphorylated tau181 predicted faster clinical progression whereas lower amyloid beta1-42 predicted faster volumetric and fractional anisotropy reduction. Neurofilament light chain and phosphorylated tau181 were of greater predictive value in patients with tau pathology as compared to TDP-43 pathology. Baseline neurofilament light chain correlated with baseline clinical severity and frontotemporal volume in behavioral variant frontotemporal dementia. Baseline total tau correlated with baseline clinical severity in semantic variant primary progressive aphasia. INTERPRETATION: High cerebrospinal fluid neurofilament light chain predicts more aggressive disease in behavioral variant frontotemporal dementia and nonfluent variant primary progressive aphasia. Total tau, phosphorylated tau181, and amyloid beta1-42 also predict some measures of disease aggressiveness in frontotemporal dementia.

2.
Neurology ; 90(4): e282-e290, 2018 01 23.
Article in English | MEDLINE | ID: mdl-29282337

ABSTRACT

OBJECTIVE: To assess the relationships between fluid and imaging biomarkers of tau pathology and compare their diagnostic utility in a clinically heterogeneous sample. METHODS: Fifty-three patients (28 with clinical Alzheimer disease [AD] and 25 with non-AD clinical neurodegenerative diagnoses) underwent ß-amyloid (Aß) and tau ([18F]AV1451) PET and lumbar puncture. CSF biomarkers (Aß42, total tau [t-tau], and phosphorylated tau [p-tau]) were measured by multianalyte immunoassay (AlzBio3). Receiver operator characteristic analyses were performed to compare discrimination of Aß-positive AD from non-AD conditions across biomarkers. Correlations between CSF biomarkers and PET standardized uptake value ratios (SUVR) were assessed using skipped Pearson correlation coefficients. Voxelwise analyses were run to assess regional CSF-PET associations. RESULTS: [18F]AV1451-PET cortical SUVR and p-tau showed excellent discrimination between Aß-positive AD and non-AD conditions (area under the curve 0.92-0.94; ≤0.83 for other CSF measures), and reached 83% classification agreement. In the full sample, cortical [18F]AV1451 was associated with all CSF biomarkers, most strongly with p-tau (r = 0.75 vs 0.57 for t-tau and -0.49 for Aß42). When restricted to Aß-positive patients with AD, [18F]AV1451 SUVR correlated modestly with p-tau and t-tau (both r = 0.46) but not Aß42 (r = 0.02). On voxelwise analysis, [18F]AV1451 correlated with CSF p-tau in temporoparietal cortices and with t-tau in medial prefrontal regions. Within AD, Mini-Mental State Examination scores were associated with [18F]AV1451-PET, but not CSF biomarkers. CONCLUSION: [18F]AV1451-PET and CSF p-tau had comparable value for differential diagnosis. Correlations were robust in a heterogeneous clinical group but attenuated (although significant) in AD, suggesting that fluid and imaging biomarkers capture different aspects of tau pathology. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that, in a clinical sample of patients with a variety of suspected neurodegenerative diseases, both CSF p-tau and [18F]AV1451 distinguish AD from non-AD conditions.


Subject(s)
Brain/diagnostic imaging , Carbolines , Neurodegenerative Diseases/cerebrospinal fluid , Neurodegenerative Diseases/diagnostic imaging , Radiopharmaceuticals , tau Proteins/cerebrospinal fluid , Aged , Amyloid beta-Peptides/cerebrospinal fluid , Area Under Curve , Biomarkers/cerebrospinal fluid , Brain/metabolism , Brain/pathology , Cross-Sectional Studies , Diagnosis, Differential , Female , Humans , Male , Middle Aged , Neurodegenerative Diseases/pathology , Peptide Fragments/cerebrospinal fluid , Phosphorylation , ROC Curve , Retrospective Studies , Severity of Illness Index
3.
Brain ; 140(8): 2104-2111, 2017 Aug 01.
Article in English | MEDLINE | ID: mdl-28899014

ABSTRACT

See Mander et al. (doi:10.1093/awx174) for a scientific commentary on this article.Sleep deprivation increases amyloid-ß, suggesting that chronically disrupted sleep may promote amyloid plaques and other downstream Alzheimer's disease pathologies including tauopathy or inflammation. To date, studies have not examined which aspect of sleep modulates amyloid-ß or other Alzheimer's disease biomarkers. Seventeen healthy adults (age 35-65 years) without sleep disorders underwent 5-14 days of actigraphy, followed by slow wave activity disruption during polysomnogram, and cerebrospinal fluid collection the following morning for measurement of amyloid-ß, tau, total protein, YKL-40, and hypocretin. Data were compared to an identical protocol, with a sham condition during polysomnogram. Specific disruption of slow wave activity correlated with an increase in amyloid-ß40 (r = 0.610, P = 0.009). This effect was specific for slow wave activity, and not for sleep duration or efficiency. This effect was also specific to amyloid-ß, and not total protein, tau, YKL-40, or hypocretin. Additionally, worse home sleep quality, as measured by sleep efficiency by actigraphy in the six nights preceding lumbar punctures, was associated with higher tau (r = 0.543, P = 0.045). Slow wave activity disruption increases amyloid-ß levels acutely, and poorer sleep quality over several days increases tau. These effects are specific to neuronally-derived proteins, which suggests they are likely driven by changes in neuronal activity during disrupted sleep.


Subject(s)
Amyloid beta-Peptides/cerebrospinal fluid , Cerebrospinal Fluid Proteins/cerebrospinal fluid , Peptide Fragments/cerebrospinal fluid , Sleep Deprivation/cerebrospinal fluid , Sleep/physiology , Actigraphy , Adult , Aged , Apolipoproteins E/genetics , Chitinase-3-Like Protein 1/cerebrospinal fluid , Female , Humans , Male , Middle Aged , Orexins/cerebrospinal fluid , Polysomnography , tau Proteins/cerebrospinal fluid
4.
J Med Chem ; 60(6): 2562-2572, 2017 03 23.
Article in English | MEDLINE | ID: mdl-28231433

ABSTRACT

Sphingosine kinase (SphK) is the major source of the lipid mediator and G protein-coupled receptor agonist sphingosine-1-phosphate (S1P). S1P promotes cell growth, survival, and migration and is a key regulator of lymphocyte trafficking. Inhibition of S1P signaling has been proposed as a strategy for treatment of inflammatory diseases and cancer. Two different formats of an enzyme-based high-throughput screen yielded two attractive chemotypes capable of inhibiting S1P formation in cells. The molecular combination of these screening hits led to compound 22a (PF-543) with 2 orders of magnitude improved potency. Compound 22a inhibited SphK1 with an IC50 of 2 nM and was more than 100-fold selective for SphK1 over the SphK2 isoform. Through the modification of tail-region substituents, the specificity of inhibition for SphK1 and SphK2 could be modulated, yielding SphK1-selective, potent SphK1/2 dual, or SphK2-preferential inhibitors.


Subject(s)
Phosphotransferases (Alcohol Group Acceptor)/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Amination , Benzimidazoles/chemistry , Benzimidazoles/pharmacology , Drug Discovery , Humans , Models, Molecular , Phosphotransferases (Alcohol Group Acceptor)/metabolism , Pyrrolidines/chemistry , Pyrrolidines/pharmacology
5.
Ann Neurol ; 80(1): 154-9, 2016 07.
Article in English | MEDLINE | ID: mdl-27129429

ABSTRACT

We hypothesized that one mechanism underlying the association between obstructive sleep apnea (OSA) and Alzheimer's disease is OSA leading to decreased slow wave activity (SWA), increased synaptic activity, decreased glymphatic clearance, and increased amyloid-ß. Polysomnography and lumbar puncture were performed in OSA and control groups. SWA negatively correlated with cerebrospinal fluid (CSF) amyloid-ß-40 among controls and was decreased in the OSA group. Unexpectedly, amyloid-ß-40 was decreased in the OSA group. Other neuronally derived proteins, but not total protein, were also decreased in the OSA group, suggesting that OSA may affect the interaction between interstitial and cerebrospinal fluid. Ann Neurol 2016;80:154-159.


Subject(s)
Amyloid beta-Peptides/cerebrospinal fluid , Central Nervous System/metabolism , Nerve Tissue Proteins/cerebrospinal fluid , Peptide Fragments/cerebrospinal fluid , Sleep Apnea, Obstructive/cerebrospinal fluid , Aged , Case-Control Studies , Female , Humans , Male , Middle Aged , Polysomnography
6.
Bioorg Med Chem Lett ; 23(4): 1120-6, 2013 Feb 15.
Article in English | MEDLINE | ID: mdl-23298810

ABSTRACT

Microsomal prostaglandin E(2) synthase-1 (mPGES-1) is a novel therapeutic target for the treatment of inflammation and pain. In the preceding letter, we detailed the discovery of clinical candidate PF-04693627, a potent mPGES-1 inhibitor possessing a novel benzoxazole structure. While PF-04693627 was undergoing further preclinical profiling, we sought to identify a back-up mPGES-1 inhibitor that differentiated itself from PF-04693627. The design, synthesis, mPGES-1 activity and in vivo PK of a novel set of substituted benzoxazoles are described herein. Also described is a conformation-based hypothesis for mPGES-1 activity based on the preferred conformation of the cyclohexane ring within this class of inhibitors.


Subject(s)
Benzoxazoles/chemistry , Benzoxazoles/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Intramolecular Oxidoreductases/antagonists & inhibitors , Benzoxazoles/chemical synthesis , Drug Design , Enzyme Inhibitors/chemical synthesis , Humans , Intramolecular Oxidoreductases/chemistry , Intramolecular Oxidoreductases/metabolism , Models, Molecular , Molecular Conformation , Prostaglandin-E Synthases , Structure-Activity Relationship
7.
Bioorg Med Chem Lett ; 23(4): 1114-9, 2013 Feb 15.
Article in English | MEDLINE | ID: mdl-23260349

ABSTRACT

Inhibition of mPGES-1, the terminal enzyme in the arachidonic acid/COX pathway to regulate the production of pro-inflammatory prostaglandin PGE2, is considered an attractive new therapeutic target for safe and effective anti-inflammatory drugs. The discovery of a novel series of orally active, selective benzoxazole piperidinecarboxamides as mPGES-1 inhibitors is described. Structure-activity optimization of lead 5 with cyclohexyl carbinols resulted in compound 12, which showed excellent in vitro potency and selectivity against COX-2, and reasonable pharmacokinetic properties. Further SAR studies of the benzoxazole ring substituents lead to a novel series of highly potent compounds with improved PK profile, including 23, 26, and 29, which were effective in a carrageenan-stimulated guinea pig air pouch model of inflammation. Based on its excellent in vitro and in vivo pharmacological, pharmacokinetic and safety profile and ease of synthesis, compound 26 (PF-4693627) was advanced to clinical studies.


Subject(s)
Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Inflammation/drug therapy , Intramolecular Oxidoreductases/antagonists & inhibitors , Drug Discovery , Humans , Inflammation/enzymology , Intramolecular Oxidoreductases/metabolism , Prostaglandin-E Synthases , Structure-Activity Relationship
8.
Bioorg Med Chem Lett ; 22(11): 3795-9, 2012 Jun 01.
Article in English | MEDLINE | ID: mdl-22546671

ABSTRACT

The inhibition of hH-PGDS has been proposed as a potential target for the development of anti-allergic and anti-inflammatory drugs. Herein we describe our investigation of the binding pocket of this important enzyme and our observation that two water molecules bind to our inhibitors and the enzyme. A series of compounds were prepared to the probe the importance of the water molecules in determining the binding affinity of the inhibitors to the enzyme. The study provides insight into the binding requirements for the design of potent hH-PGDS inhibitors.


Subject(s)
Anti-Allergic Agents/chemistry , Anti-Inflammatory Agents/chemistry , Enzyme Inhibitors/chemistry , Intramolecular Oxidoreductases/antagonists & inhibitors , Lipocalins/antagonists & inhibitors , Water/chemistry , Anti-Allergic Agents/chemical synthesis , Anti-Inflammatory Agents/chemical synthesis , Binding Sites , Computer Simulation , Crystallography, X-Ray , Enzyme Inhibitors/chemical synthesis , Humans , Intramolecular Oxidoreductases/metabolism , Isoquinolines/chemistry , Lipocalins/metabolism , Naphthalenes/chemistry , Protein Structure, Tertiary
9.
Biochem J ; 444(1): 79-88, 2012 May 15.
Article in English | MEDLINE | ID: mdl-22397330

ABSTRACT

SphK (sphingosine kinase) is the major source of the bioactive lipid and GPCR (G-protein-coupled receptor) agonist S1P (sphingosine 1-phosphate). S1P promotes cell growth, survival and migration, and is a key regulator of lymphocyte trafficking. Inhibition of S1P signalling has been proposed as a strategy for treatment of inflammatory diseases and cancer. In the present paper we describe the discovery and characterization of PF-543, a novel cell-permeant inhibitor of SphK1. PF-543 inhibits SphK1 with a K(i) of 3.6 nM, is sphingosine-competitive and is more than 100-fold selective for SphK1 over the SphK2 isoform. In 1483 head and neck carcinoma cells, which are characterized by high levels of SphK1 expression and an unusually high rate of S1P production, PF-543 decreased the level of endogenous S1P 10-fold with a proportional increase in the level of sphingosine. In contrast with past reports that show that the growth of many cancer cell lines is SphK1-dependent, specific inhibition of SphK1 had no effect on the proliferation and survival of 1483 cells, despite a dramatic change in the cellular S1P/sphingosine ratio. PF-543 was effective as a potent inhibitor of S1P formation in whole blood, indicating that the SphK1 isoform of sphingosine kinase is the major source of S1P in human blood. PF-543 is the most potent inhibitor of SphK1 described to date and it will be useful for dissecting specific roles of SphK1-driven S1P signalling.


Subject(s)
Lysophospholipids/metabolism , Phosphotransferases (Alcohol Group Acceptor)/antagonists & inhibitors , Pyrrolidines/pharmacology , Sphingosine/analogs & derivatives , Sulfones/pharmacology , Cell Line, Tumor , Cell Membrane Permeability , Humans , Lysophospholipids/blood , Methanol , Phosphorylation , Pyrrolidines/chemical synthesis , Pyrrolidines/metabolism , Sphingosine/blood , Sphingosine/metabolism , Substrate Specificity , Sulfones/chemical synthesis , Sulfones/metabolism
10.
ACS Med Chem Lett ; 1(2): 59-63, 2010 May 13.
Article in English | MEDLINE | ID: mdl-24900177

ABSTRACT

Hematopoietic prostaglandin D synthase (HPGDS) is primarly expressed in mast cells, antigen-presenting cells, and Th-2 cells. HPGDS converts PGH2 into PGD2, a mediator thought to play a pivotal role in airway allergy and inflammatory processes. In this letter, we report the discovery of an orally potent and selective inhibitor of HPGDS that reduces the antigen-induced response in allergic sheep.

11.
J Med Chem ; 47(4): 900-6, 2004 Feb 12.
Article in English | MEDLINE | ID: mdl-14761191

ABSTRACT

5(S)-Fluoro-N6-(iminoethyl)-l-lysine (14), an analogue of the potent, selective induced nitric oxide synthase (iNOS) inhibitor iminoethyl-l-lysine (1), was synthesized and found to be a selective iNOS inhibitor.


Subject(s)
Lysine/chemical synthesis , Nitric Oxide Synthase/antagonists & inhibitors , Crystallography, X-Ray , Isoenzymes/antagonists & inhibitors , Isoenzymes/chemistry , Lysine/analogs & derivatives , Lysine/chemistry , Models, Molecular , Nitric Oxide Synthase/chemistry , Nitric Oxide Synthase Type II
12.
Org Biomol Chem ; 1(20): 3527-34, 2003 Oct 21.
Article in English | MEDLINE | ID: mdl-14599013

ABSTRACT

In the literature, the introduction of fluorine into bioactive molecules has been known to enhance the biological activity relative to the parent molecule. Described in this article is the synthesis of 4R-fluoro-L-NIL (12) and 4,4-difluoro-L-NIL (23) as part of our iNOS program. Both 12 and 23 were found to be selective iNOS inhibitors as shown in Table 2 below. Secondarily, methodology to synthesize orthogonally protected 4-fluoro-L-lysine and 4,4-difluoro-L-lysine has been developed.


Subject(s)
Enzyme Inhibitors/chemistry , Fluorine/chemistry , Lysine/analogs & derivatives , Nitric Oxide Synthase/antagonists & inhibitors , Animals , Crystallography, X-Ray , Humans , Lysine/chemistry , Mice , Models, Biological , Models, Chemical , Molecular Structure , Nitric Oxide Synthase Type II
14.
J Med Chem ; 45(8): 1686-9, 2002 Apr 11.
Article in English | MEDLINE | ID: mdl-11931623

ABSTRACT

The 5-tetrazole amide of L-N(6)-(1-iminoethyl)lysine (L-NIL), L-N(6)-(1-iminoethyl)lysine 5-tetrazole amide (1), has been prepared and evaluated. In contrast to L-NIL, 1 is a stable, nonhygroscopic, crystalline solid. Unlike L-NIL, 1 has minimal inhibitory activity in vitro on human inducible nitric oxide synthase (iNOS). However, it is rapidly converted in vivo to L-NIL and produces dose-dependent inhibition of iNOS in acute and chronic models of inflammation in the rodent with efficacy comparable to L-NIL. In addition, both 1 and L-NIL exhibit significant and comparable in vivo selectivity for the inhibition of iNOS vs endothelial NOS. Doses approximately 80-fold greater than those that inhibited inflammation do not elevate systemic blood pressure. In summary, both the physical properties and the pharmacological profile of 1 make it an ideal molecule for preclinical and clinical studies on the role of selective iNOS inhibitors in mediating inflammatory disease processes.


Subject(s)
Enzyme Inhibitors/chemical synthesis , Homoarginine/chemical synthesis , Lysine/analogs & derivatives , Lysine/chemistry , Nitric Oxide Synthase/antagonists & inhibitors , Prodrugs/chemical synthesis , Acute Disease , Administration, Oral , Animals , Arthritis, Experimental/pathology , Carrageenan , Chronic Disease , Crystallization , Edema/chemically induced , Edema/enzymology , Edema/pathology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , Homoarginine/analogs & derivatives , Homoarginine/chemistry , Homoarginine/metabolism , Humans , Isoenzymes/antagonists & inhibitors , Nitric Oxide Synthase Type I , Nitric Oxide Synthase Type II , Nitric Oxide Synthase Type III , Prodrugs/chemistry , Prodrugs/metabolism , Rats , Recombinant Proteins/antagonists & inhibitors
SELECTION OF CITATIONS
SEARCH DETAIL
...