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- Gising, Johan, et al.
(författare)
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A straightforward microwave method for rapid synthesis of N-1, C-6 functionalized 3,5-dichloro-2(1H)-pyrazinones
- 2009
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Ingår i: Organic and biomolecular chemistry. - 1477-0520 .- 1477-0539. ; 7:13, s. 2809-2815
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Tidskriftsartikel (refereegranskat)abstract
- A rapid and versatile one-pot, 2 * 10 min microwave protocol for the prepn. of N-1 and C-6 decorated 3,5-dichloro-2(1H)-pyrazinones, e.g., I, from the corresponding primary amines and aldehyde was developed. Comparable reaction sequences using classical conditions require about 1-2 days of heating. The alpha -aminonitrile was first generated in a Strecker reaction and thereafter cyclized under microwave heating. The microwave approach developed offers the possibility of efficiently generating and utilizing functionalized 3-amino-5-chloro-2(1H)-pyrazinone-N-1-carboxylic acids as beta -strand inducing core structures in a medicinal chem. context. To illustrate the usefulness of the method, the synthesis of two novel 2(1H)-pyrazinone-contg. Hepatitis C virus NS3 protease inhibitors, e.g., II, is reported.
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- Örtqvist, Lisa, et al.
(författare)
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Bowel control, bladder function, and quality of life in children with cloacal malformations
- 2023
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Ingår i: Journal of Pediatric Surgery. - : Elsevier BV. - 0022-3468 .- 1531-5037. ; 58:10, s. 1942-1948
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Long-term outcomes of cloacal malformations remain unclear. We evaluated postoperative bowel control, bladder function and quality of life in patients under 18 years of age with cloaca. Materials and methods: This was a multi-center cross-sectional observational study accomplished by the Nordic Pediatric Surgery Research Consortium. Patients with a cloacal malformation, 4–17 years of age, were eligible. Data including patient characteristics, surgical procedures, and complications were retrieved from case records. Established questionnaires with normative control values evaluating bowel function, bladder function, and health-related quality of life (HRQoL) were sent to the patients and their caregivers. The study was approved by the participating center's Ethics Review Authorities. Results: Twenty-six (67%) of 39 eligible patients with median age 9.5 (range, 4–17) years responded. Twenty-one (81%) patients had a common channel ≤3 cm. Imaging confirmed sacral anomalies in 11 patients and spinal cord abnormalities in nine. Excluding patients with stoma (n = 5), median bowel function score was 12 [7-19], and 5 patients (20%) reported a bowel function score ≥17, approaching normal bowel control level. Bowel management increased proportion of socially continent school-aged children to 52%. Six (23%) patients had a permanent urinary diversion or used clean intermittent catheterization (CIC), while majority (70%) of the remaining patients were urinary continent. The reported HRQoL was comparable to healthy Swedish children. Conclusion: Whilst well-preserved spontaneous bowel control was rare, a majority of patients were dry for urine without any additional procedures. Few patients experienced social problems or negative impact on HRQoL due to bladder or bowel dysfunction. Level of evidence: Level IV.
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- Örtqvist, Pernilla, et al.
(författare)
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Discovery of Achiral Inhibitors of the Hepatitis C Virus NS3 Protease based on 2(1H)-pyrazinones
- 2010
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Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896 .- 1464-3391. ; 18:17, s. 6512-6525
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Tidskriftsartikel (refereegranskat)abstract
- Herein, the design, synthesis and inhibitory potency of a series of novel hepatitis C virus (HCV) NS3 protease inhibitors are presented. These inhibitors are based on a 2(1H)-pyrazinone P3 scaffold in combination with either a P2 phenylglycine or a glycine, and they were evaluated on the wild type as well as on two resistant variants of the enzyme, A156T and D168V. Molecular modelling suggested that the aromatic side-chain of the P2 phenylglycine occupies the same space as the substituent in position 6 on the pyrazinone core. The versatile synthetic route applied for the pyrazinone synthesis made a switch between the two positions easily feasible, resulting in phenyl- or benzyl substituted pyrazinones and leaving glycine as the P2 residue. Of several P1-P1′ residues evaluated, an aromatic P1-P1′ scaffold was found superior in combination with the new P3-P2 building block. As a result, an entirely new type of achiral and rigidified inhibitors was discovered, with the best of the novel inhibitors having fourfold improved potency compared to the corresponding tripeptide lead. We consider these achiral inhibitors highly suitable as starting points for further optimization.
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- Örtqvist, Pernilla, 1978-
(författare)
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On the Design and Synthesis of Hepatitis C Virus NS3 Protease Inhibitors : From Tripeptides to Achiral Compounds
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Infection by the hepatitis C virus (HCV) leads to inflammation of the liver, i.e. hepatitis. The acute infection often progresses to a chronic phase during which the liver function is gradually impaired. Approximately 20% of these chronic cases develop liver cirrhosis, with an ensuing increased risk of liver cancer. Global estimates of the total number of chronic cases range from 123–170 million. Yet, neither specific anti-HCV drugs nor vaccines are available. When drugs become available for daily clinical use, rapid development of drug-resistant strains is expected, making resistance an important issue. One of the most studied targets for specific anti-HCV drugs is the NS3 protease. The main objectives of the work presented in this thesis were to design and synthesise peptidomimetic inhibitors of this enzyme, and to establish the structure–activity relationships (SARs) regarding the inhibition of the wild type as well as of the known resistant variants A156T and D168V. Substituted prolines are common P2 residues in HCV NS3 protease inhibitors. To decrease the peptide character of the inhibitors, the non-coded phenylglycine was evaluated as a proline replacement in combination with known and novel P3 and P1 residues and P2 substituents. The results confirmed that phenylglycine is a promising P2 scaffold, with a possible π-stacking interaction with histidine 57 of the active site. However, to benefit from its full potential, additional optimisation is required. A 2(1H)-pyrazinone-based scaffold was introduced as P3 residue. Utilising the scope of the method developed for the pyrazinone scaffold synthesis, the phenylglycine side-chain was transferred to the scaffold. In combination with an aromatic P1 building-block, this design yielded achiral, peptidomimetic inhibitors, three times more potent than the tripeptide lead. The SARs for the inhibition of the resistant variants A156T and D168V were investigated for compounds based on either P2 proline or phenylglycine. It was concluded that the vulnerability of the inhibitors to alterations in the enzyme depends on the P2 and the P1 residue, not only on the P2 as previously suggested. These results provide important information for the design of a new generation of inhibitors with improved properties.
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- Örtqvist, Pernilla, et al.
(författare)
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Phenylglycine as a Novel P2 Scaffold in Hepatitis C Virus NS3 Protease Inhibitors
- 2007
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Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896 .- 1464-3391. ; 15:3, s. 1448-1474
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Tidskriftsartikel (refereegranskat)abstract
- Molecular modeling and inhibitory potencies of tetrapeptide protease inhibitors of HCV NS3 proposed phenylglycine as a new promising P2 residue. The results suggest that phenylglycine might be capable of interacting with the NS3 (protease-helicase/NTPase) in ways not possible for the common P2 proline-based inhibitors. Thus, a series of tripeptides, both linear and macrocyclic, based on p-hydroxy-phenylglycine in the P2 position were prepared and their inhibitory effect determined. When the p-hydroxy group was replaced by methoxy, isoquinolin-, or quinolinyloxy functions, inhibitors with improved potencies were obtained. The P2 phenylglycine-based inhibitors were further optimized by C-terminal extension to acyl sulfonamides and by P1–P3 cyclization, which gave products with inhibition constants in the nanomolar range (75 nM).
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| 9. |
- Örtqvist, Pernilla, et al.
(författare)
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Structure-activity relationships of HCV NS3 protease inhibitors evaluated on the drug-resistant variants A156T and D168V
- 2010
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Ingår i: Antiviral Therapy. - 1359-6535 .- 2040-2058. ; 15:6, s. 841-852
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: HCV infections are a serious threat to public health. An important drug target is the NS3 protease, for which several inhibitors are in clinical trials. Because of the high mutation rate of the virus, resistance against any HCV-specific drug is likely to become a substantial problem. Structure-activity data for the major resistant variants are therefore needed to guide future designs of protease inhibitors. METHODS: The inhibitory potency of tripeptide NS3 protease inhibitors, with either a P2 proline or phenylglycine, in combination with different P3 and P1-P1' groups, was assessed in enzyme activity assays using the full-length NS3 protein with known resistance-conferring substitutions A156T or D168V. The results obtained from these variants were compared with the inhibition of the wild-type enzyme. Molecular modelling was used to rationalize the biochemical results. RESULTS: Inhibitors combining the P2 proline and P1 (1R,2S)-1-amino-2-vinylcyclopropyl-carboxylic acid (vinylACCA) lost much of their potency on the resistant variants. Exchange of the P2 proline for phenylglycine yielded inhibitors that were equipotent on the wild-type and on the A156T and D168V variants. The same result was obtained from the combination of either the P2 residue with a norvaline or an aromatic scaffold in the P1 position. CONCLUSIONS: The combination of a substituted P2 proline and P1 vinylACCA appears to be the main problem behind the observed resistance. Molecular modelling suggests an enforced change in binding conformation for the P2 proline-based inhibitors, whereas the phenylglycine-based inhibitors retained their wild-type binding conformation in the substituted forms of the enzyme.
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