| 1. |
- Adrian Meredith, Jenny, 1971-, et al.
(author)
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Design and Synthesis of BACE-1 Inhibitors Containing a New Hydroxyethylene (HE) Scaffold: Potent activities in a cellular assay
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Other publication (other academic/artistic)abstract
- In a preceding report from our group we disclosed the development of a novel HE transition state isostere with a difluorophenoxymethyl side chain in the P1 position and a methoxy group in the P1’ position furnishing highly potent inhibitors of BACE-1 (i.e. lead compound 1), which moreover exhibit very promising selectivity over cathepsin D. In a continuation of this work with the aim at improving on the cell-based activity and pharmacokinetic properties, we have further developed the SAR for the P1 side chain of inhibitor 1 whereby the P1 side chain oxygen has been substituted for an amine, a carbon or a bond. The chemistry developed for the previous HE inhibitor structure 1 has now been extended to readily accommodate the introduction of new P1 side chains into this new HE scaffold. These modifications have given rise to several highly potent inhibitors where the most potent displayed a BACE-1 Ki value of 0.2 nM and a cell-based Aβ40 IC50 value of 9 nM. Thus, regarding the enzyme inhibition in the cell assay a more than 600-fold improvement compared to compound 1 was achieved via minor structural alterations.
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| 2. |
- Adrian Meredith, Jenny, 1971-, et al.
(author)
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P2 '-truncated BACE-1 inhibitors with a novel hydroxethylene-like core
- 2010
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In: European Journal of Medicinal Chemistry. - : Elsevier BV. - 0223-5234 .- 1768-3254. ; 45:2, s. 542-554
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Journal article (peer-reviewed)abstract
- Highly potent BACE-1 protease inhibitors derived from a novel hydroxyethylene-like core structure were recently developed by our group using X-ray crystal structure data and molecular modelling. In a continuation of this work guided by molecular modelling we have explored a truncated core motif where the P2' amide group is replaced by an ether linkage resulting in a set of alkoxy, aryloxy and alkylaryl groups, with the overall aim to reduce molecular weight and the number of amide bonds to increase permeability and bestow the inhibitors with drug-like features. The most potent of these inhibitors displayed a BACE-I IC50 value of 140 nM. The synthesis of these BACE-I inhibitors utilizes readily available starting materials, furnishing the target compounds in good overall yields.
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| 3. |
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| 4. |
- Björklund, Catarina, 1981-, et al.
(author)
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Design and synthesis of potent and selective BACE-1 inhibitors
- 2010
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In: Journal of Medicinal Chemistry. - : American Chemical Society. - 0022-2623 .- 1520-4804. ; 53:4, s. 1458-1464
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Journal article (peer-reviewed)abstract
- Several highly potent BACE-1 protease inhibitors have been developed from an inhibitor series containing a novel hydroxyethylene (HE) core structure displaying aryloxymethyl or benzyloxymethyl P1 side chains and a methoxy P1’ side chain. The target molecules were readily synthesized from chiral carbohydrate starting materials, furnishing the inhibitor compounds in good overall yields. The inhibitors show both high BACE-1 potency and good selectivity against cathepsin D, where the most potent inhibitor furnish a BACE-1 IC50 value of 0.32 nM and displays > 3000 fold selectivity over cathepsin D.
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| 5. |
- Björklund, Catarina, 1981-, et al.
(author)
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Discovery of Potent BACE-1 Inhibitors Containing a New Hydroxyethylene (HE) Scaffold : Exploration of P1’ Alkoxy Residues and an Aminoethylene (AE) Central Core
- 2010
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In: Bioorganic & Medicinal Chemistry. - : Elsevier Ltd.. - 0968-0896 .- 1464-3391. ; 18:4, s. 1711-1723
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Journal article (peer-reviewed)abstract
- In a preceding study we have described the development of a new hydroxyethylene (HE) core motif displaying P1 aryloxymethyl and P1’ methoxy substituents delivering potent BACE-1 inhibitors. In a continuation of this work we have now explored the SAR of the S1’ pocket by introducing a set of P1’ alkoxy groups and evaluated them as BACE-1 inhibitors. Previously the P1 and P1’ positions of the classical HE template have been relatively little explored due to the complexity of the chemical routes involved in modifications at these positions. However, the chemistries developed for the current HE template renders substituents in both the P1 and P1’ positions readily available for SAR exploration. The BACE-1 inhibitors prepared displayed IC50 values in the range of 4-45 nM, where the most potent compounds featured small P1’ groups. The cathepsin D selectivity which was high for the smallest P1’ sustituents (P1’=ethoxy, fold selectively >600) dropped for larger groups (P1’=benzyloxy, fold selectivity of 1.6). We have also confirmed the importance of both the hydroxyl group and its stereochemistry preference for this HE transition state isostere by preparing both the deoxygenated analogue and by inverting the configuration of the hydroxyl group to the R-configuration, which as expected resulted in large activity drops. Finally substituting the hydroxyl group by an amino group having the same configuration (S), which previously have been described to deliver potent BACE-1 inhibitors with advantageous properties, surprisingly resulted in a large drop in the inhibitory activity.
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| 6. |
- Gennemark, Peter, et al.
(author)
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An oral antisense oligonucleotide for PCSK9 inhibition
- 2021
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In: Science Translational Medicine. - : AMER ASSOC ADVANCEMENT SCIENCE. - 1946-6234 .- 1946-6242. ; 13:593
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Journal article (peer-reviewed)abstract
- Inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) reduce low-density lipoprotein (LDL) cholesterol and are used for treatment of dyslipidemia. Current PCSK9 inhibitors are administered via subcutaneous injection. We present a highly potent, chemically modified PCSK9 antisense oligonucleotide (ASO) with potential for oral delivery. Past attempts at oral delivery using earlier-generation ASO chemistries and transient permeation enhancers provided encouraging data, suggesting that improving potency of the ASO could make oral delivery a reality. The constrained ethyl chemistry and liver targeting enabled by N-acetylgalactosamine conjugation make this ASO highly potent. A single subcutaneous dose of 90 mg reduced PCSK9 by >90% in humans with elevated LDL cholesterol and a monthly subcutaneous dose of around 25 mg is predicted to reduce PCSK9 by 80% at steady state. To investigate the feasibility of oral administration, the ASO was coformulated in a tablet with sodium caprate as permeation enhancer. Repeated oral daily dosing in dogs resulted in a bioavailability of 7% in the liver (target organ), about fivefold greater than the plasma bioavailability. Target engagement after oral administration was confirmed by intrajejunal administration of a rat-specific surrogate ASO in solution with the enhancer to rats and by plasma PCSK9 and LDL cholesterol lowering in cynomolgus monkey after tablet administration. On the basis of an assumption of 5% liver bioavailability after oral administration in humans, a daily dose of 15 mg is predicted to reduce circulating PCSK9 by 80% at steady state, supporting the development of the compound for oral administration to treat dyslipidemia.
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| 7. |
- Hogstedt, Christer, et al.
(author)
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Cancer Incidence in a Cohort of Swedish Chimney Sweeps, 1958-2006.
- 2013
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In: American Journal of Public Health. - 1541-0048. ; 103:9, s. 1708-1714
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Journal article (peer-reviewed)abstract
- Objectives. We examined cancer incidence in an expanded cohort of Swedish chimney sweeps. Methods. We added male chimney sweep trade union members (1981-2006) to an earlier cohort (employed 1918-1980) and linked them to nationwide registers of cancer, causes of deaths, and total population. The total cohort (n = 6320) was followed from 1958 through 2006. We estimated standardized incidence ratios (SIRs) using the male Swedish population as reference. We estimated exposure as years of employment and analyzed for exposure-response associations by Poisson regression. Results. A total of 813 primary cancers were observed vs 626 expected (SIR = 1.30; 95% confidence interval = 1.21, 1.39). As in a previous follow-up, SIRs were significantly increased for cancer of the esophagus, liver, lung, bladder, and all hematopoietic cancer. New findings included significantly elevated SIRs for cancer of the colon, pleura, adenocarcinoma of the lung, and at unspecified sites. Total cancer and bladder cancer demonstrated positive exposure-response associations. Conclusions. Exposure to soot and asbestos are likely causes of the observed cancer excesses, with contributions from adverse lifestyle factors. Preventive actions to control work exposures and promote healthier lifestyles are an important priority. (Am J Public Health. Published online ahead of print January 17, 2013: e1-e7. doi:10.2105/AJPH.2012.300860).
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