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- Johannesson, Petra, et al.
(författare)
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SAR and optimization of trioxoisothiazole-based liver receptor X (LXR) agonists leading to the clinical candidate AZD3971
- 2014
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Ingår i: Division of Medicinal Chemistry. ; , s. 247-247
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Konferensbidrag (refereegranskat)abstract
- The liver X receptors (LXRα and LXRβ) are members of the nuclear receptor family of transcription factors. The activation of LXR induces genes involved in reverse cholesterol transport (RCT), which is believed to be the main effect of LXR agonists in the prevention or treatment of atherosclerosis. However LXR agonists have also been shown to cause hepatic steatosis and hypertriglyceridaemia. The ability to separate beneficial effects from negative effects has been a challenge that so far has hampered the development of LXR agonists for human use. We herein describe the SAR and optimization of a series of trioxoisothiazole-based LXR agonists leading to compounds with nanomolar potencies and a separation of beneficial versus negative effects in vivo. This work ultimately led to the nomination of AZD3971 as a candidate for the treatment of atherosclerosis.
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| 2. |
- Pemberton, Nils, et al.
(författare)
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Synthesis and Functionalization of Cyclic Sulfonimidamides : A Novel Chiral Heterocyclic Carboxylic Acid Bioisostere
- 2012
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Ingår i: ACS Medicinal Chemistry Letters. - : American Chemical Society (ACS). - 1948-5875. ; 3:7, s. 574-578
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Tidskriftsartikel (refereegranskat)abstract
- An efficient synthesis of aryl substituted cyclic sulfonimidamides designed as chiral nonplanar heterocyclic carboxylic acid bioisosteres is described. The cyclic sulfonimidamide ring system could be prepared in two steps from a trifluoroacetyl protected sulfinamide and methyl ester protected amino acids. By varying the amino acid, a range of different C-3 substituted sulfonimidamides could be prepared. The compounds could be further derivatized in the aryl ring using standard cross coupling reactions to yield highly substituted cyclic sulfonimidamides in excellent yields. The physicochemical properties of the final compounds were examined and compared to those of the corresponding carboxylic acid and tetrazole derivatives. The unique nonplanar shape in combination with the relatively strong acidity (pK(a) 5-6) and the ease of modifying the chemical structure to fine-tune the physicochemical properties suggest that this heterocycle can be a valuable addition to the range of available carboxylic acid isosteres.
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| 3. |
- Bergström, Emma, et al.
(författare)
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An interactive shared Reading intervention designed for preverbal infants : A feasibility study exploring early language and cognitive development
- 2024
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Ingår i: Child Language Teaching and Therapy. - : Sage Publications. - 0265-6590 .- 1477-0865.
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Tidskriftsartikel (refereegranskat)abstract
- Creating an environment suitable for language acquisition through shared reading significantly contributes to improving a child's language development and parent–child relationship. Reading in an interactive way, such as dialogic reading, is favorable. Nevertheless, dialogic reading is designed for children above the age of two and shared reading is recommended to start during the child's first year. The present study aimed to explore the feasibility of an interactive shared reading intervention, inspired by dialogic reading, where the reading techniques were designed to complement infants’ preverbal developmental level. The study further intended to explore its preliminary effect on infants’ cognitive and language development. Eleven parent–infant dyads participated, bi-monthly, in four in-depth intervention sessions where the shared reading techniques were modeled. Between sessions, parents and infants engaged in shared reading using these techniques. Post-intervention interviews served to reflect the feasibility of the intervention. Infant cognitive and language assessments were conducted pre- and post-intervention using BAYLEY-III and CSBS DP ITC. Favorable results regarding feasibility and infant language development were found, however, for cognitive development the results were non-significant. We discuss clinical considerations and the scope for conducting future studies.
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| 4. |
- Bratt, Emma, et al.
(författare)
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A General Suzuki Cross-Coupling Reaction of Heteroaromatics Catalyzed by Nanopalladium on Amino-Functionalized Siliceous Mesocellular Foam
- 2014
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Ingår i: Journal of Organic Chemistry. - : American Chemical Society (ACS). - 0022-3263 .- 1520-6904. ; 79:9, s. 3946-3954
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Tidskriftsartikel (refereegranskat)abstract
- Suzuki-Miyaura cross-coupling reactions of heteroaromatics catalyzed by palladium supported in the cavities of amino-functionalized siliceous mesocellular foam are presented. The nanopalladium catalyst effectively couples not only heteroaryl halides with boronic acids but also heteroaryl halides with boronate esters, potassium trifluoroborates, MIDA boronates, and triolborates, producing a wide range of heterobiaryls in good to excellent yields. Furthermore, the heterogeneous palladium nanocatalyst can easily be removed from the reaction mixture by filtration and recycled several times with minimal loss in activity. This catalyst provides an alternative, environmentally friendly, low-leaching process for the preparation of heterobiaryls.
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| 5. |
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| 6. |
- Bratt, Sorosh, et al.
(författare)
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Bleeding is associated with severely impaired outcomes in surgery for acute type a aortic dissection
- 2024
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Ingår i: SCANDINAVIAN CARDIOVASCULAR JOURNAL. - 1401-7431 .- 1651-2006. ; 58:1
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Tidskriftsartikel (refereegranskat)abstract
- Background. Surgery for acute type A aortic dissection confers a risk for significant bleeding. We analyzed the impact of massive bleeding on complications after surgery for acute type A aortic dissection. Methods. Patients undergoing surgery for acute type A aortic dissection from the retrospective multicenter Nordic Consortium for Acute Type A Aortic Dissection (NORCAAD) database 2005-2014 were eligible. Massive bleeding was defined according to the Universal Definition of Perioperative Bleeding. The primary outcome measure was early mortality and secondary outcome measures were perioperative stroke, mechanical ventilation more than 48 h, new-onset dialysis, and intensive care unit stay. Propensity score matching was performed to adjust for differences in covariates. Results. Nine hundred ninety-seven patients were included, of whom 403 (40.4%) had massive bleeding. In the propensity score-matched cohort (344 pairs), patients with massive bleeding had higher 30-day mortality (17.2 versus 7.6%, p < .001), mechanical ventilation more than 48 h (52.8 versus 22.6%, p < .001), perioperative stroke (24.3 versus 14.8%, p = .002), new-onset dialysis (22.5 versus 4.9%, p < .001), and longer intensive care unit stay (6 versus 3 days, p < .001), compared with patients without massive bleeding. Risk factors for massive bleeding were previous cardiac surgery, preoperative clopidogrel or ticagrelor therapy, DeBakey type I dissection, and localized or generalized malperfusion. Conclusions. Massive bleeding in surgery for acute type A aortic dissection is associated with a markedly increased risk for severe complications as well as early death. Further improvement of surgical technique and pharmacological optimization of coagulation is paramount to possibly improve outcomes in acute type A aortic dissection repair.
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