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- Björklund, Catarina, 1981-
(författare)
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Design and Synthesis of BACE-1 Inhibitors : Novel Compounds Targeting an Aspartic Protease Important in the Pathogenesis of Alzheimer’s Disease
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis deals with the design and synthesis of protease inhibitors targeting the aspartic protease BACE-1 (β-site APP cleaving enzyme-1), an enzyme important in the pathogenesis of Alzheimer’s disease. The inhibitors are evaluated with respect to inhibition data, in a structure-activity relationship part. Alzheimer’s disease is a disabling, progressive and ultimately fatal form of dementia afflicting approximately 40 percent of the population over 80 years, with over 30 million people suffering from Alzheimer’s disease worldwide. This makes Alzheimer’s disease the most common form of dementia. The identification of the amyloid-β peptide (Aβ) as the main constituent of extracellular plaques, which characterize Alzheimer’s disease, suggests that Aβ plays a vital role in the pathology of Alzheimer’s disease. The formation of Aβ occurs when amyloid-β precursor protein (APP) is cleaved by β-secretase (BACE-1) and γ-secretase, which differ in length by 39-42 amino acids. This suggests that β-secretase is a suitable target for the development of therapeutics against Alzheimer’s disease. The synthetic work of this thesis comprises development of BACE-1 inhibitors containing a hydroxyethylene (HE) central core transition state isostere. The target molecules were readily synthesized from chiral carbohydrate starting materials. Highly potent inhibitors were produced by varying the substituents coupled to the HE central core. Selecting an aryloxymethyl P1 side-chain and a methoxy P1’ side-chain resulted in exceptionally potent BACE-1 inhibitors that also exhibit high selectivity over cathepsin D. In a further development, the ether oxygen linkage in the P1 side-chain was removed, resulting in a carba analogue, providing improved potency in a cell-based assay.
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| 2. |
- Bäck, Marcus, et al.
(författare)
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Novel potent macrocyclic inhibitors of the hepatitis C virus NS3 protease : use of cyclopentane and cyclopentene P2-motifs
- 2007
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Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896 .- 1464-3391. ; 15:22, s. 7184-7202
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Tidskriftsartikel (refereegranskat)abstract
- Several highly potent novel HCV NS3 protease inhibitors have been developed from two inhibitor series containing either a P2 trisubstituted macrocyclic cyclopentane- or a P2 cyclopentene dicarboxylic acid moiety as surrogates for the widely used N-acyl-(4R)-hydroxyproline in the P2 position. These inhibitors were optimized for anti HCV activities through examination of different ring sizes in the macrocyclic systems and further by exploring the effect of P4 substituent removal on potency. The target molecules were synthesized from readily available starting materials, furnishing the inhibitor compounds in good overall yields. It was found that the 14-membered ring system was the most potent in these two series and that the corresponding 13-, 15-, and 16-membered macrocyclic rings delivered less potent inhibitors. Moreover, the corresponding P1 acylsulfonamides had superior potencies over the corresponding P1 carboxylic acids. It is noteworthy that it has been possible to develop highly potent HCV protease inhibitors that altogether lack the P4 substituent. Thus the most potent inhibitor described in this work, inhibitor 20, displays a Ki value of 0.41 nM and an EC50 value of 9 nM in the subgenomic HCV replicon cell model on genotype 1b. To the best of our knowledge this is the first example described in the literature of a HCV protease inhibitor displaying high potency in the replicon assay and lacking the P4 substituent, a finding which should facilitate the development of orally active small molecule inhibitors against the HCV protease.
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| 5. |
- Dahlgren, Anders, et al.
(författare)
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Novel morpholinone-based D-Phe-Pro-Arg mimics as potential thrombin inhibitors : design, synthesis, and X-ray crystal structure of an enzyme inhibitor complex
- 2002
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Ingår i: Bioorganic & Medicinal Chemistry. - 0968-0896 .- 1464-3391. ; 10:6, s. 1829-1839
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Tidskriftsartikel (refereegranskat)abstract
- A morpholinone structural motif derived from d(+)- and l(−)-malic acid has been used as a mimic of d-Phe-Pro in the thrombin inhibiting tripeptide d-Phe-Pro-Arg. In place of Arg the more rigid P1 truncated p-amidinobenzylamine (Pab) or 2-amino-5-aminomethyl-3-methyl-pyridine have been utilized. The synthetic strategy developed readily delivers these novel thrombin inhibitors used to probe the α-thrombin inhibitor binding site. The best candidate in this series of thrombin inhibitors exhibits an in vitro IC50 of 720 nM. The X-ray crystal structure of this candidate co-crystallized with α-thrombin is discussed.
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| 6. |
- Ekegren, Jenny K, et al.
(författare)
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Microwave-accelerated synthesis of P1'-extended HIV-1 protease inhibitors encompassing a tertiary alcohol in the transition-state mimicking scaffold
- 2006
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 49:5, s. 1828-1832
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Tidskriftsartikel (refereegranskat)abstract
- Two series of P1'-extended HIV-1 protease inhibitors comprising a tertiary alcohol in the transition-state mimic exhibiting Ki values ranging from 2.1 to 93 nM have been synthesized. Microwave-accelerated palladium-catalyzed cross-couplings were utilized to rapidly optimize the P1' side chain. High cellular antiviral potencies were encountered when the P1' benzyl group was elongated with a 3- or 4-pyridyl substituent (EC50 = 0.18-0.22 microM). X-ray crystallographic data were obtained for three inhibitors cocrystallized with the enzyme.
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| 10. |
- Johansson, Per-Ola, et al.
(författare)
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Design and synthesis of potent inhibitors of plasmepsin I and II : x-ray crystal structure of inhibitor in complex with plasmepsin II
- 2005
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 48:13, s. 4400-4409
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Tidskriftsartikel (refereegranskat)abstract
- New and potent inhibitors of the malarial aspartic proteases plasmepsin (Plm) I and II, from the deadliest malaria parasite Plasmodium falciparum, have been synthesized utilizing Suzuki coupling reactions on previously synthesized bromobenzyloxy-substituted statine-like inhibitors. The enzyme inhibition activity has been improved up to eight times by identifying P1 substituents that effectively bind to the continuous S1-S3 crevice of Plasmepsin I and II. By replacement of the bromo atom in the P1 p-bromobenzyloxy-substituted inhibitors with different aryl substituents, several inhibitors exhibiting Ki values in the low nanomolar range for both Plm I and II have been identified. Some of these inhibitors are also effective in attenuating parasite growth in red blood cells, with the best inhibitors, compounds 2 and 4, displaying 70% and 83% inhibition, respectively, at a concentration of 5 μM. The design was partially guided by the X-ray crystal structure disclosed herein of the previously synthesized inhibitor 1 in complex with plasmepsin II. © 2005 American Chemical Society.
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