| 1. |
- Weber, Tobias A, et al.
(författare)
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γ-Secretase modulators show selectivity for γ-secretase-mediated amyloid precursor protein intramembrane processing.
- 2022
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Ingår i: Journal of cellular and molecular medicine. - : Wiley. - 1582-4934 .- 1582-1838. ; 26:3, s. 880-892
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Tidskriftsartikel (refereegranskat)abstract
- The aggregation of β-amyloid peptide 42 results in the formation of toxic oligomers and plaques, which plays a pivotal role in Alzheimer's disease pathogenesis. Aβ42 is one of several Aβ peptides, all of Aβ30 to Aβ43 that are produced as a result of γ-secretase-mediated regulated intramembrane proteolysis of the amyloid precursor protein. γ-Secretase modulators (GSMs) represent a promising class of Aβ42-lowering anti-amyloidogenic compounds for the treatment of AD. Gamma-secretase modulators change the relative proportion of secreted Aβ peptides, while sparing the γ-secretase-mediated processing event resulting in the release of the cytoplasmic APP intracellular domain. In this study, we have characterized how GSMs affect the γ-secretase cleavage of three γ-secretase substrates, E-cadherin, ephrin type A receptor 4 (EphA4) and ephrin type B receptor 2 (EphB2), which all are implicated in important contexts of cell signalling. By using a reporter gene assay, we demonstrate that the γ-secretase-dependent generation of EphA4 and EphB2 intracellular domains is unaffected by GSMs. We also show that γ-secretase processing of EphA4 and EphB2 results in the release of several Aβ-like peptides, but that only the production of Aβ-like proteins from EphA4 is modulated by GSMs, but with an order of magnitude lower potency as compared to Aβ modulation. Collectively, these results suggest that GSMs are selective for γ-secretase-mediated Aβ production.
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| 2. |
- Besidski, Yevgeni, et al.
(författare)
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Preparation of azetidinotriazole compounds as gamma secretase modulators useful for treatment of Aβ-related diseases.
- 2014
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Patent (populärvet., debatt m.m.)abstract
- The invention relates to azetidinotriazole compds. of formula I and pharmaceutically acceptable salts and pharmaceutical compns. thereof, as well as processes for making these compds. for use in the treatment and/or prevention of Aβ-related diseases. I [wherein A is (un)substituted 5- or 6-membered heteroaryl ring comprising at least one N; R1 is H, C1-3-alkyl, cyano, etc.; R2 is (un)substituted C1-6-alkyl, C3-7-cycloalkyl-C1-3-alkyl, heterocyclyl-C1-3-alkyl, etc.; R3, R5, and R7 are each independently selected from H, (un)substituted C1-3-alkyl, C3-7-cycloalkyl, etc.; R4, R6, R8 are each independently selected from H, F, C1-3-alkyl, etc.; or R3 and R4, or R5 and R6, or R7 and R8, together with the carbon to which they are attached, form (un)substituted 3- to 7-membered satd. ring optionally contg. an O or N] or pharmaceutically acceptable salts thereof are claimed and exemplified. Example compd. II was prepd. from the reaction of III with 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline under Buchwald-Hartwig conditions in 26% yield. Nine compds. of I were evaluated for activity on Aβ formation utilizing electrochemiluminescence anal. and HEK cells expressing amyloid precursor protein (data given). [on SciFinder(R)]
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| 3. |
- Engström, Sven, et al.
(författare)
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Hög personlig läkarkontinuitet i primärvård förenad med färre besök på akutmottagning : En populationsbaserad studie i Jönköpings sjukvårdsregion
- 2019
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Ingår i: Läkartidningen. - : Läkartidningen Förlag. - 0023-7205 .- 1652-7518. ; 116:51-52
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Tidskriftsartikel (refereegranskat)abstract
- HUVUDBUDSKAPHög personlig läkarkontinuitet i primärvård var förenad med lägre antal läkarbesök på akutmottagningar.Sambandet mellan hög personlig läkarkontinuitet och lägre antal läkarbesök på akutmottagning var störst för gruppen yngre vuxna.God tillgänglighet till läkarbesök på vårdcentral var inte förenad med lägre antal akutmottagningsbesök.God tillgänglighet till telefonrådgivning av sjuksköterska på vårdcentral var inte förenad med lägre antal akutmottagningsbesök.
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| 4. |
- Engström, Sven, et al.
(författare)
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Hög personlig läkarkontinuitet i primärvård förenad med färre besök på akutmottagning [Personal physician continuity in primary care associated with fewer emergency room visits]
- 2019
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Ingår i: Läkartidningen. - Stockholm, Sweden : Sveriges Läkarförbund. - 0023-7205 .- 1652-7518. ; 116
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Tidskriftsartikel (refereegranskat)abstract
- Overloading of the emergency departments in hospitals is, in Sweden, a common problem that is often blamed on lack of access to primary care. We have conducted a cross-sectional study comprising more than 40% of the 347 837 inhabitants of Region Jönköping with access to complete individual data on healthcare consumption, personal doctor continuity, socio-economics, and accessibility data for all of the regions health centres. Individuals with high personal continuity at their own health centre had significantly fewer emergency room visits compared to those with the lowest continuity: for younger adults 55% and for elderly 34% fewer emergency room visits. Access to doctor consultations or to counselling nurses in primary care was not associated with a lower number of emergency room visits. Our results show the importance of personal doctor continuity also for the group of younger adults.
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| 5. |
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| 6. |
- Fransson, Rebecca, et al.
(författare)
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Exploration and pharmacokinetic profiling of phenylalanine based carbamates as novel substance p 1-7 analogues
- 2014
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Ingår i: ACS Medicinal Chemistry Letters. - : American Chemical Society (ACS). - 1948-5875. ; 5:12, s. 1272-1277
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Tidskriftsartikel (refereegranskat)abstract
- The bioactive metabolite of Substance P, the heptapeptide SP1-7 (H-Arg-Pro-Lys-Pro-Gln-Gln-Phe-OH), has been shown to attenuate signs of hyperalgesia in diabetic mice, which indicate a possible use of compounds targeting the SP1-7 binding site as analgesics for neuropathic pain. Aiming at the development of drug-like SP1-7 peptidomimetics we have previously reported on the discovery of H-Phe-Phe-NH2 as a high affinity lead compound. Unfortunately, the pharmacophore of this compound was accompanied by a poor pharmacokinetic (PK) profile. Herein, further lead optimization of H-Phe-Phe-NH2 by substituting the N-terminal phenylalanine for a benzylcarbamate group giving a new type of SP1-7 analogues with good binding affinities is reported. Extensive in vitro as well as in vivo PK characterization is presented for this compound. Evaluation of different C-terminal functional groups, i.e., hydroxamic acid, acyl sulfonamide, acyl cyanamide, acyl hydrazine, and oxadiazole, suggested hydroxamic acid as a bioisosteric replacement for the original primary amide.
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| 7. |
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| 8. |
- Jonsson, Anna, 1981-, et al.
(författare)
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Small constrained SP1-7 analogues bind to a unique site and promote anti-allodynic effects following systemic injection in mice
- 2015
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Ingår i: Neuroscience. - : Elsevier BV. - 0306-4522 .- 1873-7544. ; 298, s. 112-119
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Tidskriftsartikel (refereegranskat)abstract
- Previous results have shown that the substance P (SP) N-terminal fragment SP1–7 may attenuate hyperalgesia and produce anti-allodynia in animals using various experimental models for neuropathic pain. The heptapeptide was found to induce its effects through binding to and activating specific sites apart from any known neurokinin or opioid receptor. Furthermore, we have applied a medicinal chemistry program to develop lead compounds mimicking the effect of SP1–7. The present study was designed to evaluate the pharmacological effect of these compounds using the mouse spared nerve injury (SNI) model of chronic neuropathic pain. Also, as no comprehensive screen with the aim to identify the SP1–7 target has yet been performed we screened our lead compound H-Phe-Phe-NH2 toward a panel of drug targets. The extensive target screen, including 111 targets, did not reveal any hit for the binding site among a number of known receptors or enzymes involved in pain modulation. Our animal studies confirmed that SP1–7, but also synthetic analogs thereof, possesses anti-allodynic effects in the mouse SNI model of neuropathic pain. One of the lead compounds, a constrained H-Phe-Phe-NH2 analog, was shown to exhibit a significant anti-allodynic effect.
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| 9. |
- Juréen, P., et al.
(författare)
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Wild-type MIC distributions for aminoglycoside and cyclic polypeptide antibiotics used for treatment of Mycobacterium tuberculosis infections
- 2010
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Ingår i: Journal of Clinical Microbiology. - : American Society for Microbiology. - 0095-1137 .- 1098-660X. ; 48:5, s. 1853-1858
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Tidskriftsartikel (refereegranskat)abstract
- The aminoglycosides and cyclic polypeptides are essential drugs in the treatment of multidrug-resistant tuberculosis, underscoring the need for accurate and reproducible drug susceptibility testing (DST). The epidemiological cutoff value (ECOFF) separating wild-type susceptible strains from non-wild-type strains is an important but rarely used tool for indicating susceptibility breakpoints against Mycobacterium tuberculosis. In this study, we established wild-type MIC distributions on Middlebrook 7H10 medium for amikacin, kanamycin, streptomycin, capreomycin, and viomycin using 90 consecutive clinical isolates and 21 resistant strains. Overall, the MIC variation between and within runs did not exceed +/-1 MIC dilution step, and validation of MIC values in Bactec 960 MGIT demonstrated good agreement. Tentative ECOFFs defining the wild type were established for all investigated drugs, including amikacin and viomycin, which currently lack susceptibility breakpoints for 7H10. Five out of seven amikacin- and kanamycin-resistant isolates were classified as susceptible to capreomycin according to the current critical concentration (10 mg/liter) but were non-wild type according to the ECOFF (4 mg/liter), suggesting that the critical concentration may be too high. All amikacin- and kanamycin-resistant isolates were clearly below the ECOFF for viomycin, and two of them were below the ECOFF for streptomycin, indicating that these two drugs may be considered for treatment of amikacin-resistant strains. Pharmacodynamic indices (peak serum concentration [Cmax]/MIC) were more favorable for amikacin and viomycin compared to kanamycin and capreomycin. In conclusion, our data emphasize the importance of establishing wild-type MIC distributions for improving the quality of drug susceptibility testing against Mycobacterium tuberculosis.
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| 10. |
- Nordvall, Gunnar, et al.
(författare)
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Analogs of the Muscarinic Agent 2'‑Methylspiro(1‑azabicyclo[2.2.2]octane)‑3,4'‑[1,3]dioxolane (AF30) : Synthesis and Pharmacology
- 1992
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 35:9, s. 1541-1550
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Tidskriftsartikel (refereegranskat)abstract
- A number of tetrahydrofuran analogues of 2'-methylspiro[1-azabicyclo[2.2.2]octane-3,4'-[1,3]dioxolane] ( 1) have been prepared with the aim to obtain information about the relative importance of each of the oxygens in 1 for efficacy and for selectivity. In addition, the dimethyl and deamethyl doguea of 1 &re prepared. The new compounds were compared to cis- and trans-1 with regard to their ability to displace (-)-[3H]-3-quinuclidinyl benzilate ((-)-[3H]QNB) from muscarinic receptors in cerebral cortex, heart, parotid gland, and urinary bladder from guinea pigs. Functioinal studies were made on isolated guinea pig bladder and ileum. The new compounds exhibited both lower affmity and efficacy thancis-1.Aconformational studywasperformed,and the effects of steric and electronic factors on the biological activity of the compounds are discussed.
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| 11. |
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| 12. |
- Nordvall, Gunnar, et al.
(författare)
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Preparation of piperazinyl quinazolines as 5-HT6 modulators.
- 2007
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Patent (populärvet., debatt m.m.)abstract
- Title compds. represented by the formula I [wherein Q = (hetero)arylalkyl, (hetero)cycloalkylalkyl or alkyl; B = CH or N; R1 = H, OH, halo, alkyl, etc.; R2 = H, (halo)alkyl, aminocarbonylalkyl, etc.; R3 = H, (halo)alkyl or alkylaryl; R4 = CN, halo, alkoxy, etc.; m = 0-2; n = 0-4; and pharmaceutically acceptable salts, solvates or solvated salts thereof] were prepd. as 5-HT6 modulators. For example, reaction of 2,4-dichloroquinazoline with benzenesulfonamide and followed by reaction with N-methylpiperazine, gave N-[2-(4-methylpiperazin-1-yl)quinazolin-4-yl]benzenesulfonamide in 6% yield. The radioligand binding assay showed II having Ki of 1.4 nM. Thus, I and their pharmaceutical compns. are useful for the treatment of 5-HT6 mediated disorders, such as Alzheimer's disease, schizophrenia, obesity or Parkinson's disease. [on SciFinder(R)]
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| 13. |
- Nordvall, Gunnar, et al.
(författare)
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Preparation of piperazinyl quinazolines as 5-HT6 modulators.
- 2007
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Patent (populärvet., debatt m.m.)abstract
- Title compds. represented by the formula I [wherein Q = (hetero)arylalkyl; R1 = OH, halo, alkyl, etc.; R2, R3 = independently H, (halo)alkyl, aminocarbonylalkyl, etc.; n = 0-3; and pharmaceutically acceptable salts, solvates or solvated salts thereof] were prepd. as 5-HT6 modulators. For example, reaction of 2-chloro-4-(4-methylpiperazin-1-yl)quinazoline with N-methyl-4-chlorobenzenesulfonamide gave II in 10% yield. The radioligand binding assay showed II having Ki of 200 nM. Thus, I and their pharmaceutical compns. are useful for the treatment of 5-HT6 mediated disorders, such as Alzheimer's disease, schizophrenia, obesity or Parkinson's disease. [on SciFinder(R)]
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| 14. |
- Ängeby, Kristian A., et al.
(författare)
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Wild-type MIC distributions of four fluoroquinolones active against Mycobacterium tuberculosis in relation to current critical concentrations and available pharmacokinetic and pharmacodynamic data
- 2010
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Ingår i: Journal of Antimicrobial Chemotherapy. - : Oxford University Press (OUP). - 0305-7453 .- 1460-2091. ; 65:5, s. 946-952
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: To describe wild-type distributions of the MIC of fluoroquinolones for Mycobacterium tuberculosis in relation to current critical concentrations used for drug susceptibility testing and pharmacokinetic/pharmacodynamic (PK/PD) data. METHODS: A 96-stick replicator on Middlebrook 7H10 medium was used to define the MICs of ciprofloxacin, ofloxacin, moxifloxacin and levofloxacin for 90 consecutive clinical strains and 24 drug-resistant strains. The MICs were compared with routine BACTEC 460 susceptibility results and with MIC determinations in the BACTEC MGIT 960 system in a subset of strains using ofloxacin as a class representative. PK/PD data for each drug were reviewed in relation to the wild-type MIC distribution. RESULTS: The wild-type MICs of ciprofloxacin, ofloxacin, moxifloxacin and levofloxacin were distributed from 0.125 to 1, 0.25 to 1, 0.032 to 0.5 and 0.125 to 0.5 mg/L, respectively. The MIC data correlated well with the BACTEC 960 MGIT and BACTEC 460 results. PD indices were the most favourable for levofloxacin, followed by moxifloxacin, ofloxacin and ciprofloxacin. CONCLUSIONS: We propose S (susceptible)
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