| 1. |
- RABOISSON, P. J. B., et al.
(author)
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PYRIMIDINE SUBSTITUTED MACROCYCLIC HCV INHIBITORS
- 2008
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Patent (pop. science, debate, etc.)abstract
- Compounds of the Formula (I) including a stereoisomer thereof, or an N-oxide, a pharmaceutically acceptable addition salt, or a pharmaceutically acceptable addition solvate thereof; useful as HCV inhibitors; processes for preparing these compounds as well as pharmaceutical compositions comprising these compounds as active ingredient.
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| 2. |
- Andersson, H.O., et al.
(author)
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Optimization of P1-P3 groups in symmetric and asymmetric HIV-1 protease inhibitors
- 2003
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In: European Journal of Biochemistry. - : Wiley. - 0014-2956 .- 1432-1033. ; 270:8, s. 1746-1758
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Journal article (peer-reviewed)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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| 5. |
- Oscarsson, K, et al.
(author)
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Solid phase assisted synthesis of HIV-1 protease inhibitors. Expedient entry to unsymmetrical substitution of a C-2 symmetric template
- 2000
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In: Canadian journal of chemistry (Print). - 0008-4042 .- 1480-3291. ; 78:6, s. 829-837
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Journal article (peer-reviewed)abstract
- A solid phase synthesis has been developed leading up to unsymmetrical HIV-1 protease inhibitors that are not readily available by conventional solution phase chemistry (18a-g). To prepare these compounds the hydroxyl group of (1S,2R)-(-)-cis-1-phthalimido-2-indanol (3) was coupled to a Merrifield resin via a dihydropyrane linker. Cleavage of the phthalimido protecting group and reaction of the liberated amine with the bis-activated symmetrical diacid 15 resulted in the resin bound amide 16. Coupling of 16 with amino acids and amines followed by hydrolysis produced the desired unsymmetrical products 18a-g from which potent HIV-1 protease inhibitors were identified, e.g., 18e (k(i) = 0.1 nM), 18a (k(i) = 0.2 nM) and 18c (k(i) = 2 nM).
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| 7. |
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| 8. |
- Wachtmeister, J., et al.
(author)
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Impact of the central hydroxyl groups on the activity of symmetrical HIV-1 protease inhibitors derived from L-mannaric acid
- 2000
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In: Tetrahedron. - 0040-4020 .- 1464-5416. ; 56:20, s. 3219-3225
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Journal article (peer-reviewed)abstract
- The influence of the central hydroxyl groups on the anti-viral activity of symmetrical HIV-1 protease inhibitors derived from L-mannaric acid has been examined. L-Iditol was synthesized and used as a chiral precursor for the synthesis of the corresponding inhibitor with inverted configuration at C-3 and C-4. Key intermediates were 3,4-O-isopropylidene-L-iditol and the activated L-idaric acid succinimidyI ester. The configurations of the central hydroxyl groups required for optimal inhibition of the HIV-1 protease were determined to be the C-3R and C-4R, i.e. the L-manno-configuration. Three C2-symmetric inhibitors were converted to their thiocarbonates and reduced to provide the corresponding hydroxyethyl transition-state mimics. Deletion of the C-4 hydroxyl group in these inhibitors gave no further improvement in the anti-viral activity. (C) 2000 Published by Elsevier Science Ltd.
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| 9. |
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| 10. |
- Ayesa, S., et al.
(author)
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CYSTEINE PROTEASE INHIBITORS
- 2011
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Patent (pop. science, debate, etc.)abstract
- Compounds of the formula IwhereinR1a is H; and R1b is C1-C6 alkyl, Carbocyclyl or Het; orR1a and R1b together define a saturated cyclic amine with 3-6 ring atoms;R2a and R2b are H, halo, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy; orR2a and R2b together with the carbon atom to which they are attached form a C3-C6cycloalkyl;R3 is a branched C5-C10alkyl chain, C2-C4haloalkyl or C3-C7cycloalkylmethyl,R4 is Het, Carbocyclyl,optionally substituted as defined in the specification and pharmaceutically acceptable salts,hydrates and N-oxides thereof; are inhibitors of cathepsin S and have utility in the treatment of psoriasis, autoimmune disorders and other disorders such as asthma, arteriosclerosis, COPD and chronic pain.
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