| 1. |
- Adrian Meredith, Jenny, 1971-, et al.
(författare)
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Design and synthesis of novel P2 substituents in diol-based HIV protease inhibitors
- 2010
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Ingår i: European Journal of Medicinal Chemistry. - : Elsevier BV. - 0223-5234 .- 1768-3254. ; 45:1, s. 160-170
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Tidskriftsartikel (refereegranskat)abstract
- The synthesis and SAR of HIV-1 protease inhibitors containing novel P2 structural elements are presented. The inhibitors were designed having hydrogen bond accepting P2 substituents to probe potential favorable interactions to Asp-29/Asp-30 of the HIV-1 protease backbone utilizing inhibitor 3 as a model template. Several inhibitors were synthesized from an L-Val methyl amide P2 motif by appending hydrogen bonding moieties from either the isopropyl side-chain or from the methyl amide portion. The most promising inhibitors 4a and 4e displayed K-i values of 1.0 nM and 0.7 nM respectively and EC50 values in the MT4 cell-based assay of 0.17 mu M and 0.33 mu M respectively, a slight loss in potency compared to lead inhibitor 3. These inhibitors were also tested against an HIV protease inhibitor resistant strain carrying the M461, V82F, and 184V mutations. Inhibitors 4a and 4e displayed a 3 and 4 fold change respectively compared with HIV wild type, whereas lead inhibitor 3 showed a higher 9 fold change. This study further demonstrate the chemical tractability of the approach where various P2 substituents can be introduced in just one chemical step from lactone 21 enabling facile modifications of the overall properties in this inhibitor class.
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| 2. |
- Brännström, Mats, 1958, et al.
(författare)
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One uterus bridging three generations: first live birth after mother-to-daughter uterus transplantation
- 2016
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Ingår i: Fertility and Sterility. - : Elsevier BV. - 0015-0282 .- 1556-5653. ; 106:2, s. 261-266
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To determine whether a uterus from the mother of a woman with absolute uterine factor infertility can be transplanted to daughter and carry a pregnancy with delivery of a healthy child. Patient(s): Twenty eight-year-old woman with uterine agenesis, her male partner, and her 50-year-old mother. Intervention(s): In vitro fertilization with embryo cryopreservation before live donor uterus transplantation (UTx). Induction immunosuppression. Embryo transfer 12 months after UTx, pregnancy controls, delivery, and hysterectomy. Main Outcome Measure(s): Results of IVF-ET, parameters of pregnancy/birth, and surgical data of transplantation/cesarean section/hysterectomy. Result(s): Two IVF cycles before UTx resulted in 10 cryopreserved embryos. Donor surgery included hysterectomy with vascular pedicles of uterine vessels and proximal vessels up to and including parts of internal iliacs. Recipient surgery was by bilateral vascular connections to external iliacs, vaginal-vaginal anastomosis, and uterine fixation. Pregnancy occurred at the first single ET, and the pregnancy proceeded uneventfully until gestational week 34, when the patient developed cholestasis with intense pruritus. Cesarean section was performed at 34+6, with delivery of a healthy boy (weight 2,335 g). Hysterectomy was performed 3.5 months after delivery. The weight of the healthy child at 12 months was 9.3 kg. Grandmother (uterus donor) and mother are in good health 3 years after UTx. Conclusion(s): This is the first report of a live birth after mother-to-daughter UTx, and it also represents the second birth ever after human UTx. (C) 2016 by American Society for Reproductive Medicine.
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| 3. |
- 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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| 4. |
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| 5. |
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| 6. |
- De Rosa, Maria, et al.
(författare)
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Synthesis of P1 '-Functionalized Macrocyclic Transition-State Mimicking HIV-1 Protease Inhibitors Encompassing a Tertiary Alcohol
- 2014
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 1520-4804 .- 0022-2623. ; 57:15, s. 6444-6457
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Tidskriftsartikel (refereegranskat)abstract
- Seven novel tertiary alcohol containing linear HIV-1 protease inhibitors (PIs), decorated at the para position of the benzyl group in the P1' side with (hetero)aromatic moieties, were synthesized and biologically evaluated. To study the inhibition and antiviral activity effect of P1-P3 macro-cyclization, 14- and 15-membered macrocyclic Pis were prepared by ring-closing metathesis of the corresponding linear PIs. The macrocycles were more active than the linear precursors and compound 101, with a 2-thiazoly1 group in the P1' position, was the most potent PI of this new series (K-1 2.2 nM, EC50 0.2 mu M). Co-crystallized complexes of both linear and macrocyclic PIs with the HIV-1 protease enzyme were prepared and analyzed.
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| 7. |
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| 8. |
- Ekegren, Jenny K, et al.
(författare)
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A new class of HIV-1 protease inhibitors containing a tertiary alcohol in the transition-state mimicking scaffold
- 2005
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 48:25, s. 8098-8102
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Tidskriftsartikel (refereegranskat)abstract
- Novel HIV-1 protease inhibitors encompassing a tertiary alcohol as part of the transition-state mimicking unit have been synthesized. Variation of the P1‘−P3‘ residues and alteration of the tertiary alcohol absolute stereochemistry afforded 10 inhibitors. High potencies for the compounds with (S)-configuration at the carbon carrying the tertiary hydroxyl group were achieved with Ki values down to 2.4 nM. X-ray crystallographic data for a representative compound in complex with HIV-1 protease are presented.
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| 9. |
- 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. |
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| 11. |
- Ekegren, Jenny, et al.
(författare)
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Variations of the P2 Group in HIV-1 Protease Inhibitors Containing a Tertiary Alcohol in the Transition-State Mimicking Scaffold
- 2006
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Ingår i: Organic and biomolecular chemistry. - : Royal Society of Chemistry (RSC). - 1477-0520 .- 1477-0539. ; 4:16, s. 3040-3043
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Tidskriftsartikel (refereegranskat)abstract
- The development of synthetic protocol leading to HIV-1 protease inhibitors with a tertiary alcohol based transition-state mimicking unit and different P2 side chains was investigated. (2S)-2-benztloxirane-2-carboxylic acid ((S)-5) was used as a key intermediate in the synthesis of the new HIV-1 protease inhibitors. (S)-5 was coupled with different amines using EDC, NMM, and HOBT, resulting in the corresponding amides at low to moderate yields. The observation supports the hypothesis that intramolecular hydrogen bonding to the tertiary alcohol in the transition-state mimic is present in these molecules. Purification by reverse-phase LC-MS resulted in moderate to good yields of most target compounds. The HIV-1 protease inhibition data suggest that the size and polarity of the P2 substituent are crucial to allow proper accommodation in the S2 sub-site.
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| 12. |
- Forsblad-d'Elia, Helena, et al.
(författare)
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Cardiac conduction system abnormalities in ankylosing spondylitis : a cross-sectional study.
- 2013
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Ingår i: BMC Musculoskeletal Disorders. - : Springer Science and Business Media LLC. - 1471-2474. ; 14, s. 237-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Cardiac conduction disturbances are common in spondyloarthropathies such as ankylosing spondylitis (AS). Whether their occurrence can be linked to signs and symptoms of rheumatic disease activity is an unsettled issue addressed in this study.METHODS: In this cross-sectional study patients with AS according to modified New York criteria but without psoriasis, inflammatory bowel disease, dementia, pregnancy, other severe diseases such as malignancy and difficulties in answering questionnaires were invited; and 210 participated (120 men), mean age 49 years (SD 13; range: 16-77). Questionnaires, physical examination, ECG, and laboratory tests were performed at the same visit.RESULTS: Cardiac conduction disturbances were common and diagnosed in 10-33%, depending on if conservative or less conservative predefined criteria were applied. They consisted mostly of 1st degree atrio-ventricular block and prolonged QRS duration, but one patient had a pacemaker and 7 more had complete bundle branch blocks. Conduction abnormalities were associated mainly with age, male gender and body weight, and not with laboratory measures of inflammation or with Bath Ankylosing Spondylitis Disease Activity Index. Neither were they associated with the presence of HLA B27, which was found in 87% of all patients; the subtype B270502 dominated in all patients.CONCLUSIONS: Cardiac conduction abnormalities are common in AS, but not associated with markers of disease activity or specific B27 subtypes. Even relatively mild conduction system abnormalities might, however, indirectly affect morbidity and mortality.
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| 13. |
- Gossas, Thomas, et al.
(författare)
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The advantage of biosensor analysis over enzyme inhibition studies for slow dissociating inhibitors : characterization of hydroxamate-based matrix metalloproteinase-12 inhibitors
- 2013
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Ingår i: MedChemComm. - : Royal Society of Chemistry (RSC). - 2040-2503 .- 2040-2511. ; 4:2, s. 432-442
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Tidskriftsartikel (refereegranskat)abstract
- The kinetic characteristics of hydroxamate-based inhibitors of matrix metalloproteinase (MMP)-12 were explored using an SPR biosensor-based assay and enzyme inhibition analysis. These high-affinity inhibitors were shown to dissociate very slowly from the enzyme-inhibitor complex while a carboxylate analogue had a much faster dissociation rate, verifying the importance of the hydroxamate group for the slow dissociation. Progress curve enzyme inhibition analysis confirmed that the hydroxamate compounds but not the carboxylate compound acted as time-dependent inhibitors. The slow dissociation excluded steady-state estimation of IC50-values and K-i values but also made K-i values from progress curve analysis unreliable. Although a full characterization of the inhibitors using biosensor analysis was limited by slow dissociation, it provided kinetic and mechanistic information of relevance for MMP drug discovery and avoided some pitfalls of conventional enzyme inhibition assays.
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| 14. |
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| 15. |
- Henriksson, Jan, et al.
(författare)
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Per-Olof Åstrand : Nekrolog
- 2015
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Annan publikation (populärvet., debatt m.m.)abstract
- Nekrolog över Per-Olof ÅstrandProfessor emeritus Per-Olof Åstrand har avlidit i en ålder av 92 år. Hans närmaste anhöriga är makan Irma och barnen Elin och Per med familjer.Per-Olof Åstrand föddes i Bredaryd i Småland den 21 oktober 1922, och avled den 2 januari 2015 i Näsby Park norr om Stockholm. Efter värnplikt och beredskapstjänstgöring i pansartrupperna under andra världskriget kom han 1944 till Kungl. Gymnastiska Centralinstitutet (GCI/GIH) för studier till gymnastiklärare. Vid sluttentamen i fysiologi var hans svar så avancerade att den ansvarige läraren bad professorn, Erik Hohwü Christensen, att rätta dem. Kort därefter fick GCI:s fysiologiska institution en ny amanuens.Efter gymnastikdirektörsexamen 1946 följde läkarstudier, och parallellt med dessa inleddes avhandlingsarbetet ”Experimental studies of physical working capacity in relation to sex and age”, som försvarades 1952. Genom detta utvecklades en metodik för att mäta maximal syreupptagning. Det blev en avgörande variabel att relatera till i hans senare forskning om den cirkulatoriska och respiratoriska anpassningen till fysiskt arbete och träning. Det submaximala konditionstest som P.-O., och hans blivande hustru Irma Ryhming, publicerade år 1954 bidrog till att göra GCI känt över världen. Det finns fog att benämna honom som ”den vetenskapligt baserade konditionsträningens fader”. 1970 blev han professor i kroppsövningarnas fysiologi vid GIH.P.-O. visade tidigt ett stort intresse för undervisning, och många mötte honom i populärvetenskapliga skrifter såsom ”Kondition och hälsa” och ”Bättre kondition”, men det var genom den omfattande läroboken ”Textbook of Work Physiology: Physiological Bases for Exercise”, skriven tillsammans med Kaare Rodahl, som han blev det riktigt stora namnet inom internationell arbetsfysiologi. Där framträdde holisten Åstrand med en bredd och ett djup som ingen förr hade fångat och skrivit fram. Denna bok, P.-O:s pedagogiska förmåga och engagemang har haft avgörande betydelse för många studenter och kolleger.Hans gärningar gjorde honom till ledamot i många lärda sällskap och hedersdoktor vid ett antal universitet ute i världen. Därtill var han en hedersman, med en personlighet präglad av en stor omtanke, slagkraftig humor och generös spiritualitet, ofta med inslag av en särpräglad musikalisk förmåga. För oss som studenter och lärare vid GIH kom samvaron med P.-O. ofta att formas till högtidsstunder. En legendar har nu lämnat oss i djupaste sorg, men också i tacksamhet över allt han bidrog med i våra liv.Jan HenrikssonHans RosdahlPeter SchantzHarriet Wallberg
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| 16. |
- Joshi, Advait, et al.
(författare)
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Design and Synthesis of P1-P3 Macrocyclic Tertiary-Alcohol-Comprising HIV-1 Protease Inhibitors
- 2013
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 56:22, s. 8999-9007
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Tidskriftsartikel (refereegranskat)abstract
- To study P1-P3 macrocyclizations of previously reported tertiary-alcohol-comprising HIV-1 protease inhibitors (PIs), three new 14- and 15-member macrocyclic PIs were designed, synthesized by ring-closing metathesis, and evaluated alongside with 10 novel linear PIs. Cocrystallized complexes of the macrocyclic PIs and the HIV-1 protease are presented, analyzed, and discussed. The macrocyclic structures exhibited higher activities than the linear precursors with K-i and EC50 values down to 3.1 nM and 0.37 mu M, respectively.
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| 17. |
- Mahalingam, A. Kannan, et al.
(författare)
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HIV-1 Protease Inhibitors with a Transition-State Mimic Comprising a Tertiary Alcohol : Improved Antiviral Activity in Cells
- 2010
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 53:2, s. 607-615
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Tidskriftsartikel (refereegranskat)abstract
- By a small modification in the core structure of the previously reported series of HIV-1 protease inhibitors that encompasses a tertiary alcohol as part of the transition-state mimicking scaffold, up to 56 times more potent compounds were obtained exhibiting EC50 values down to 3 nM. Three of the inhibitors also displayed excellent activity against selected resistant isolates of HIV-1. The synthesis of 25 new and optically pure HIV-1 protease inhibitors is reported, along with methods for elongation of the inhibitor Pl' side chain using microwave-accelerated, palladium-catalyzed cross-coupling reactions, the biological evaluation, and X-ray data obtained from one of the most potent analogues cocrystallized with both the wild type and the L63P, V82T, 184 V mutant of the HIV-1 protease.
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| 18. |
- Nordström, Helena, et al.
(författare)
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Identification of MMP-12 Inhibitors by Using Biosensor-Based Screening of a Fragment Library
- 2008
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 51:12, s. 3449-3459
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Tidskriftsartikel (refereegranskat)abstract
- Small inhibitors of matrix metalloproteinase 12 (MMP-12) have been identified with a biosensor-based screening strategy and a specifically designed fragment library. The interaction between fragments and three variants of the target and a reference protein with an active-site zinc ion was measured continuously by surface plasmon resonance. The developed experimental design overcame the inherent instability of MMP-12 and allowed the identification of fragments that interacted specifically with the active-site of MMP-12 but not with the reference protein. The interaction with MMP-12 for selected compounds were analyzed for concentration dependence and saturability. Compounds interacting distinctly with the target were further evaluated by an activity-based assay, verifying MMP-12 inhibition. Two effective inhibitors were identified, and the compound with highest affinity was confirmed to be a competitive inhibitor with an IC50 of 290 nM and a ligand efficiency of 0.7 kcal/mol heavy atom. This procedure integrates selectivity and binding site identification into the screening procedure and does not require structure determination.
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| 19. |
- Tolmachev, Vladimir, et al.
(författare)
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The influence of Bz-DOTA and CHX-AaEuro(3)-DTPA on the biodistribution of ABD-fused anti-HER2 Affibody molecules : implications for In-114m-mediated targeting therapy
- 2009
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 36:9, s. 1460-1468
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Tidskriftsartikel (refereegranskat)abstract
- Affibody molecules represent a novel class of high-affinity agents for radionuclide tumour targeting. Fusion of the Affibody molecules with an albumin-binding domain (ABD) enables modification of the blood kinetics of the Affibody molecules and reduction of the renal dose. Lu-177-CHX-AaEuro(3)-DTPA-ABD-(Z(HER2:342))(2), an anti-HER2 Affibody molecule-ABD fusion protein has earlier demonstrated promising results in treatment of HER2-expressing micro-xenografts in mice. The use of the in vivo generator In-114m/In-114 as a label for ABD-fused Affibody molecules would create preconditions for efficient treatment of both micrometastases (due to conversion and Auger electrons of In-114m) and bulky tumours (due to high-energy beta particles from the daughter nuclide In-114). The goal of this study was to investigate if different chelators influence the biodistribution of ABD-(Z(HER2:342))(2) and to find an optimal chelator for attachment of In-114m to the Affibody molecule-ABD fusion protein. Isothiocyanate derivatives of Bz-DOTA and CHX-AaEuro(3)-DTPA were coupled to ABD-(Z(HER2:342))(2). The cellular processing of both conjugates was studied in vitro. The influence of chelators on the biodistribution was investigated in mice using double isotope (In-114m and In-111) labelling. The apparent affinity of CHX-AaEuro(3)-DTPA-ABD-(Z(HER2:342))(2) and Bz-DOTA-ABD-(Z(HER2:342))(2) to the extracellular domain of HER2 was similar, 13.5 and 15.0 pM, respectively. It was found that both conjugates were internalized by SKOV-3 cells. The use of CHX-AaEuro(3)-DTPA provided better cellular retention of the radioactivity, better tumour accumulation of radioactivity and better tumour to organ dose ratios than Bz-DOTA-ABD-(Z(HER2:342))(2). CHX-AaEuro(3)-DTPA is more suitable for In-114m labelling of Affibody molecule-ABD fusion proteins for radionuclide therapy.
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| 20. |
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| 21. |
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| 22. |
- Wallmo, Henrik, 1977, et al.
(författare)
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The influence of hemicelluloses during the precipitation of lignin in kraft black liquor
- 2009
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Ingår i: Nordic Pulp & Paper Research Journal. - 0283-2631 .- 2000-0669. ; 24:2, s. 165-171
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Tidskriftsartikel (refereegranskat)abstract
- Removing lignin from black liquor is one way of recovering valuable organic substances for alternative use as well as reducing the energy surplus in a modern, energy-optimised kraft pulp mill. By using the recently developed "LignoBoost" process it is possible to upgrade black liquor streams of different origin to form valuable chemicals. In this investigation a combination of membrane filtration and the LignoBoost concept was used. The primary objective of the work was to investigate whether or not the filtration properties of the black liquor were affected by its hemicellulose content. The hemicellulose content in the black liquors was lowered prior to precipitation using three different pre-treatment techniques, and the filtration properties were compared to the reference black liquors of evaporated softwood and hardwood black liquor. The pre-treatment methods used were heat-treatment, ultrafiltration and a combination of ultrafiltration and nanofiltration. It was shown that the filtration resistance was lowered considerably when the hemicellulose content in the black liquor was reduced prior to precipitation. The experiments also showed that it was possible to produce a hardwood lignin product of high purity i.e. low sodium (0.2 w-% of TIDS) and hemicellulose content (0.7 w-% of TDS)
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| 23. |
- Wu, Xiongyu, et al.
(författare)
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Synthesis, X-ray Analysis, and Biological Evaluation of a New Class of Stereopure Lactam-Based HIV-1 Protease Inhibitors
- 2012
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 55:6, s. 2724-2736
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Tidskriftsartikel (refereegranskat)abstract
- In an effort to identify a new class of druglike HIV-1 protease inhibitors, four different stereopure beta-hydroxy gamma-lactam-containing inhibitors have been synthesized, biologically evaluated, and cocrystallized. The impact of the tether length of the central spacer (two or three carbons) was also investigated. A compound with a shorter tether and (3R,4S) absolute configuration exhibited high activity with a K-i of 2.1 nM and an EC50 of 0.64 mu M. Further optimization by decoration of the P1' side chain furnished an even more potent HIV-1 protease inhibitor (K-i = 0.8 nM, EC50 = 0.04 mu M). According to X-ray analysis, the new class of inhibitors did not fully succeed in forming two symmetric hydrogen bonds to the catalytic aspartates. The crystal structures of the complexes further explain the difference in potency between the shorter inhibitors (two-carbon spacer) and the longer inhibitors (three-carbon spacer).
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| 24. |
- Wu, Xiongyu, et al.
(författare)
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Two-carbon-elongated HIV-1 protease inhibitors with a tertiary-alcohol-containing transition-state mimic
- 2008
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 51:4, s. 1053-1057
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Tidskriftsartikel (refereegranskat)abstract
- A new generation of HIV-1 protease inhibitors encompassing a tertiary-alcohol-based transition-state mimic has been developed. By elongation of the core structure of recently reported inhibitors with two carbon atoms and by varying the P1' group of the compounds, efficient inhibitors were obtained with Ki down to 2.3 nM and EC50 down to 0.17 microM. Two inhibitor-enzyme X-ray structures are reported.
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| 25. |
- Öhrngren, Per, et al.
(författare)
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Hiv-1 Protease Inhibitors with a Tertiary Alcohol Containing a Transition-State Mimic and Various P2/P1´ Substituents
- 2011
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Ingår i: MedChemComm. - : Royal Society of Chemistry (RSC). - 2040-2503 .- 2040-2511. ; 2:8, s. 701-709
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Tidskriftsartikel (refereegranskat)abstract
- Two series, including in total 18 novel HIV-1 protease inhibitors, comprising a tertiary alcohol as thetransition-state mimic have been synthesised and evaluated. Replacement of the previously used, butmetabolically unstable, indanol amide group with amino acid derived aliphatic P2–P3 moietiesprovided potent inhibitors with low Ki- and EC50-values (2.7 nM and 2.0 mM, respectively). The P10subunit was varied using 10 different aromatic and heteroaromatic substituents furnishing thecorresponding inhibitors with retained activity. Permeability and stability studies showed examples inthe same range as Atazanavir. X-Ray crystallographic analysis of two selected inhibitor enzyme cocomplexes(9a and 9d) supplied detailed structural information. The binding modes were compared tothose of Atazanavir and a previously reported indanol amide containing inhibitor (14). The novelinhibitors with an elongated P1' side chain enabled a previously unexploited edge-on interaction withPhe53/153. Exchange of the previously used indanol amide P2 moiety, with a tert-leucine derived P2–P3side chain, furnished small main chain displacements in the S2–S3 pocket. The methyl amide in the P3 position caused a 2 Å shift of the Arg8/108 in comparison to 14, indicating the flexibility of the proteaseactive site.
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