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| 2. |
- Andersson, H.O., et al.
(författare)
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Optimization of P1-P3 groups in symmetric and asymmetric HIV-1 protease inhibitors
- 2003
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Ingår i: European Journal of Biochemistry. - : Wiley. - 0014-2956 .- 1432-1033. ; 270:8, s. 1746-1758
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Tidskriftsartikel (refereegranskat)abstract
- HIV-1 protease is an important target for treatment of AIDS, and efficient drugs have been developed. However, the resistance and negative side effects of the current drugs has necessitated the development of new compounds with different binding patterns. In this study, nine C-terminally duplicated HIV-1 protease inhibitors were cocrystallised with the enzyme, the crystal structures analysed at 1.8-2.3 Å resolution, and the inhibitory activity of the compounds characterized in order to evaluate the effects of the individual modifications. These compounds comprise two central hydroxy groups that mimic the geminal hydroxy groups of a cleavage-reaction intermediate. One of the hydroxy groups is located between the d-oxygen atoms of the two catalytic aspartic acid residues, and the other in the gauche position relative to the first. The asymmetric binding of the two central inhibitory hydroxyls induced a small deviation from exact C2 symmetry in the whole enzyme-inhibitor complex. The study shows that the protease molecule could accommodate its structure to different sizes of the P2/P2' groups. The structural alterations were, however, relatively conservative and limited. The binding capacity of the S3/S3' sites was exploited by elongation of the compounds with groups in the P3/P3' positions or by extension of the P1/P1' groups. Furthermore, water molecules were shown to be important binding links between the protease and the inhibitors. This study produced a number of inhibitors with Ki values in the 100 picomolar range.
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| 4. |
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| 5. |
- Wan, Y., et al.
(författare)
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Design, synthesis, and biological evaluation of the first selective nonpeptide AT2 receptor agonist
- 2004
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Ingår i: J Med Chem. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 47:24, s. 5995-6008
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Tidskriftsartikel (refereegranskat)abstract
- The first druglike selective angiotensin II AT(2) receptor agonist (21) with a K(i) value of 0.4 nM for the AT(2) receptor and a K(i) > 10 microM for the AT(1) receptor is reported. Compound 21, with a bioavailability of 20-30% after oral administration and a half-life estimated to 4 h in rat, induces outgrowth of neurite cells, stimulates p42/p44(mapk), enhances in vivo duodenal alkaline secretion in Sprague-Dawley rats, and lowers the mean arterial blood pressure in anesthetized, spontaneously hypertensive rats. Thus, the peptidomimetic 21 exerts a similar biological response as the endogenous peptide angiotensin II after selective activation of the AT(2) receptor. Compound 21, derived from the prototype nonselective AT(1)/AT(2) receptor agonist L-162,313 will serve as a valuable research tool, enabling studies of the function of the AT(2) receptor in more detail.
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| 6. |
- Bengtson, A, et al.
(författare)
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Fast synthesis of aryl triflates with controlled microwave heating
- 2002
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Ingår i: Organic Letters. - Uppsala Univ, Dept Organ Pharmaceut Chem, BMC, SE-75123 Uppsala, Sweden. : American Chemical Society (ACS). - 1523-7060 .- 1523-7052. ; 4:7, s. 1231-1233
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Tidskriftsartikel (refereegranskat)abstract
- [GRAPHICS] Synthesis of aryl triflates from phenols using N-phenyltriflimide requires only 6 min for completion when conducted with controlled microwave heating. The methodology was applied to both solution- and solid-phase conditions. Ten different aryl triflates were synthesized and isolated in good yields. Applications in high-throughput chemistry are suggested.
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| 7. |
- Bengtson, A, et al.
(författare)
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Protected indanones by a Heck-Aldol annulation reaction
- 2002
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Ingår i: Journal of Organic Chemistry. - Uppsala Univ, Dept Organ Pharmaceut Chem, SE-75123 Uppsala, Sweden. : American Chemical Society (ACS). - 0022-3263 .- 1520-6904. ; 67:16, s. 5854-5856
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Tidskriftsartikel (refereegranskat)abstract
- Monoprotected 3-hydroxyindan-1-ones have been prepared in moderate to good yields by a new tandem reaction involving salicylaldehyde triflates and commercially available 2-hydroxyethyl vinyl ether. This one-pot annulation reaction proceeds in the presence of a palladium bidentate catalyst and results in the formation of two new ring systems.
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| 8. |
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| 9. |
- Dahlgren, Anders, et al.
(författare)
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New inhibitors of the malaria aspartyl proteases plasmepsin I and II
- 2003
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Ingår i: Bioorganic & Medicinal Chemistry. - 0968-0896 .- 1464-3391. ; 11:16, s. 3423-3437
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Tidskriftsartikel (refereegranskat)abstract
- New inhibitors of plasmepsin I and II, the aspartic proteases of the malaria parasite Plasmodium falciparum, are described. From paralell solution phase chemistry, several reversed-statine type isostere inhibitors, many of which are aza-peptides, have been prepared. The synthetic strategy delivers the target compounds in good to high overall yields and with excellent stereochemical control throughout the developed route. The final products were tested for their plasmepsin I and II inhibiting properties and were found to exhibit modest but promising activity. The best inhibitor exhibits Ki values of 250 nM and 1.4 µM for Plm I and II, respectively. © 2003 Elsevier Ltd. All rights reserved.
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| 10. |
- Dahlgren, Anders, et al.
(författare)
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Solid-phase library synthesis of reversed-statine type inhibitors of the malarial aspartyl proteases plasmepsin I and II
- 2003
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Ingår i: Bioorganic & Medicinal Chemistry. - 0968-0896 .- 1464-3391. ; 11:6, s. 827-841
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Tidskriftsartikel (refereegranskat)abstract
- With the aim to develop inhibitors of the plasmepsin I and II aspartic proteases of the malaria parasite Plasmodium falciparum, we have synthesized sets of libraries from novel reversed-statine isosteres, using a combination of solution phase and solid phase chemistry. The synthetic strategy furnishes the library compounds in good to high overall yields and with excellent stereochemical control throughout the developed route. The products were evaluated for their plasmepsin I and II inhibiting properties and were found to exhibit modest but promising activity. The best inhibitor exhibits an in vitro activity of 28% inhibition of plasmepsin II at an inhibitor concentration of 0.5 µM (Ki for Plm II=5.4 µM). © 2003 Elsevier Science Ltd. All rights reserved.
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