| 1. |
- Besidski, Yevgeni, et al.
(författare)
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Preparation of aminotriazole compounds as gamma secretase modulators useful for treatment of Aβ-related diseases.
- 2014
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Patent (populärvet., debatt m.m.)abstract
- The invention relates to aminotriazole compds. of formula I and pharmaceutically acceptable salts and pharmaceutical compns. thereof, as well as processes for making these compds. for use in the treatment and/or prevention of Aβ-related diseases. I [wherein A is (un)substituted 5- or 6-membered heteroaryl ring comprising at least one N; R1 is H, C1-3-alkyl, cyano, etc.; R2 is (un)substituted C1-6-alkyl, C3-7-cycloalkyl-C1-3-alkyl, heterocyclyl-C1-3-alkyl, etc.; R3 and R4 are each independently selected from H, C1-6-alkyl, (un)substituted C3-7-cycloalkyl, etc.] or pharmaceutically acceptable salts thereof are claimed and exemplified. Example compd. II was prepd. from the reaction of 3-bromo-N-(cyclopropylmethyl)-1-methyl-1H-1,2,4-triazol-5-amine with 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline dihydrochloride under Buchwald-Hartwig conditions in 26% yield. Nine compds. of I were evaluated for inhibition of Aβ formation utilizing electrochemiluminescence anal. and HEK cells expressing amyloid precursor protein (data given). [on SciFinder(R)]
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| 2. |
- Gybaeck, Helena, et al.
(författare)
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Benzoic acid derivatives as glycine receptor inhibitors, their preparation, pharmaceutical compositions, and use in therapy.
- 2006
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Patent (populärvet., debatt m.m.)abstract
- The invention relates to benzoic acid derivs. of formula I, which are inhibitors of glycine receptors (GlyRs). In compds. I, Y is H, OH, halo, (un)substituted C1-6 alkoxy, or (un)substituted C1-6 alkyl; R1 is (un)substituted C3-6 cycloalkyl, (un)substituted heterocyclyl, (un)substituted aryl, (un)substituted alkylaryl, (un)substituted heteroaryl, or (un)substituted C3-6 alkyl; L is selected from a bond, heteroarylene, -C(O)-, -CH2-, -CH(OR4)-, -N(OH)-, -N(R4)-, -S(O)n-, where R4 is H or C1-6 alkyl and n is 0, 1, or 2; R2 is H, halo, cyano, dimethylamino, (un)substituted C1-6 alkyl, (un)substituted C3-6 cycloalkyl, (un)substituted heterocyclyl, (un)substituted aryl, (un)substituted alkylaryl, (un)substituted heterocyclyl or (un)substituted heteroaryl; and R3 is OH or C1-6 alkoxy; with the exclusion of several compds. The invention also relates to the prepn. of I, pharmaceutical compns. comprising a therapeutically effective amt. of a compd. I with one or more pharmaceutically acceptable diluents, excipients and/or inert carriers, as well as to the use of the compns. for the treatment of conditions that respond to glycine receptor inhibition, such as neuropathic or inflammatory pain syndromes. Chlorination of 4-methoxybenzenethiol followed by C-substitution with 3-tert-butyl-2-hydroxy-6-methylbenzoic acid and oxidn. gave (arylsulfonyl)benzoic acid II. Several compds. of the invention expressed IC50 values against human GlyR α1 of about 10 nM to about 30 μM (no specific data). [on SciFinder(R)]
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| 3. |
- Ladds, Marcus J. G. W., et al.
(författare)
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A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage
- 2018
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- The development of non-genotoxic therapies that activate wild-type p53 in tumors is of great interest since the discovery of p53 as a tumor suppressor. Here we report the identification of over 100 small-molecules activating p53 in cells. We elucidate the mechanism of action of a chiral tetrahydroindazole (HZ00), and through target deconvolution, we deduce that its active enantiomer (R)-HZ00, inhibits dihydroorotate dehydrogenase (DHODH). The chiral specificity of HZ05, a more potent analog, is revealed by the crystal structure of the (R)-HZ05/DHODH complex. Twelve other DHODH inhibitor chemotypes are detailed among the p53 activators, which identifies DHODH as a frequent target for structurally diverse compounds. We observe that HZ compounds accumulate cancer cells in S-phase, increase p53 synthesis, and synergize with an inhibitor of p53 degradation to reduce tumor growth in vivo. We, therefore, propose a strategy to promote cancer cell killing by p53 instead of its reversible cell cycle arresting effect.
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| 4. |
- Nordeman, Patrik, Docent, et al.
(författare)
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Automated GMP-production of α-[11 C]methyl-L-tryptophan using a tracer production system (TPS)
- 2018
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Ingår i: Journal of labelled compounds & radiopharmaceuticals. - : Wiley. - 0362-4803 .- 1099-1344. ; 61:14, s. 1106-1109
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Tidskriftsartikel (refereegranskat)abstract
- The radiosynthesis and GMP validation of [11 C]AMT for human use are described. Three consecutive batches were produced giving 940-3790 MBq (4%-17% RCY, decay corrected, based on [11 C]CO2 ) of the tracer. The molar activity at the end of synthesis was 19 to 35 GBq/μmol, the radiochemical purity was ≥98%, and the enantiomeric purity was >99%. While the synthesis method was automated using a new generation of synthesis equipment, tracer production system developed in house, the method should be readily applicable to other synthesis platforms with minor modifications.
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| 5. |
- Nordvall, Gunnar, et al.
(författare)
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Preparation of piperazinyl quinazolines as 5-HT6 modulators.
- 2007
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Patent (populärvet., debatt m.m.)abstract
- Title compds. represented by the formula I [wherein Q = (hetero)arylalkyl, (hetero)cycloalkylalkyl or alkyl; B = CH or N; R1 = H, OH, halo, alkyl, etc.; R2 = H, (halo)alkyl, aminocarbonylalkyl, etc.; R3 = H, (halo)alkyl or alkylaryl; R4 = CN, halo, alkoxy, etc.; m = 0-2; n = 0-4; and pharmaceutically acceptable salts, solvates or solvated salts thereof] were prepd. as 5-HT6 modulators. For example, reaction of 2,4-dichloroquinazoline with benzenesulfonamide and followed by reaction with N-methylpiperazine, gave N-[2-(4-methylpiperazin-1-yl)quinazolin-4-yl]benzenesulfonamide in 6% yield. The radioligand binding assay showed II having Ki of 1.4 nM. Thus, I and their pharmaceutical compns. are useful for the treatment of 5-HT6 mediated disorders, such as Alzheimer's disease, schizophrenia, obesity or Parkinson's disease. [on SciFinder(R)]
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| 6. |
- Nordvall, Gunnar, et al.
(författare)
-
Preparation of piperazinyl quinazolines as 5-HT6 modulators.
- 2007
-
Patent (populärvet., debatt m.m.)abstract
- Title compds. represented by the formula I [wherein Q = (hetero)arylalkyl; R1 = OH, halo, alkyl, etc.; R2, R3 = independently H, (halo)alkyl, aminocarbonylalkyl, etc.; n = 0-3; and pharmaceutically acceptable salts, solvates or solvated salts thereof] were prepd. as 5-HT6 modulators. For example, reaction of 2-chloro-4-(4-methylpiperazin-1-yl)quinazoline with N-methyl-4-chlorobenzenesulfonamide gave II in 10% yield. The radioligand binding assay showed II having Ki of 200 nM. Thus, I and their pharmaceutical compns. are useful for the treatment of 5-HT6 mediated disorders, such as Alzheimer's disease, schizophrenia, obesity or Parkinson's disease. [on SciFinder(R)]
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| 7. |
- Popova, Gergana, et al.
(författare)
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Optimization of Tetrahydroindazoles as Inhibitors of Human Dihydroorotate Dehydrogenase and Evaluation of Their Activity and In Vitro Metabolic Stability
- 2020
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 63:8, s. 3915-3934
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Tidskriftsartikel (refereegranskat)abstract
- Human dihydroorotate dehydrogenase (DHODH), an enzyme in the de novo pyrimidine synthesis pathway, is a target for the treatment of rheumatoid arthritis and multiple sclerosis and is re-emerging as an attractive target for cancer therapy. Here we describe the optimization of recently identified tetrahydroindazoles (HZ) as DHODH inhibitors. Several of the HZ analogues synthesized in this study are highly potent inhibitors of DHODH in an enzymatic assay, while also inhibiting cancer cell growth and viability and activating p53-dependent transcription factor activity in a reporter cell assay. Furthermore, we demonstrate the specificity of the compounds toward the de novo pyrimidine synthesis pathway through supplementation with an excess of uridine. We also show that induction of the DNA damage marker gamma-H2AX after DHODH inhibition is preventable by cotreatment with the pancaspase inhibitor Z-VAD-FMK. Additional solubility and in vitro m etabolic stability profiling revealed compound 51 as a favorable candidate for preclinical efficacy studies.
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| 8. |
- Stroem, Peter, et al.
(författare)
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Tritium labeling of a class of spirooxazaindolamines possessing analgesic properties.
- 2004
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Ingår i: Synth. Appl. Isot. Labelled Compd., Proc. Int. Symp., 8th. ; , s. 285-288
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Konferensbidrag (refereegranskat)abstract
- In order to study the mol. action of a class of spirooxazaindolamines with promising analgesic activity, tritiated material was prepd. Efficient synthesis of 3H-labeled material allowed essential information on the mol. mechanism for this class of compds. to be obtained. Different approaches for the introduction of the 3H-label on the spirooxazaindole skeleton via 3H-methyliodide were evaluated involving lithium-mediated coupling, zinc-mediated coupling and Stille coupling. Tritiation using 3H2 (g) with a Pd-catalyst was also tested. [on SciFinder(R)]
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| 9. |
- Wensbo, David, et al.
(författare)
-
Preparation of five-membered heterocyclic compounds as mGluR5 receptor antagonists.
- 2004
-
Patent (populärvet., debatt m.m.)abstract
- The present invention relates to five-membered heterocyclic compds. (shown as I; variables defined below; e.g. II), a process for their prepn. and new intermediates prepd. therein, pharmaceutical formulations contg. said compds. and to the use of said compds. in therapy, e.g. neurol., psychiatric and chronic and acute pain disorders (no data). Typical IC50 values for mGluR5 receptor antagonist activity are ≤10 μM; no values for individual compds. are given. Methods of prepn. are claimed and example prepns. and/or characterization data are included for ∼800 examples of I and intermediates. For example, [3-[3-[[[4-methyl-5-(thiophen-2-yl)-4H-[1,2,4]triazol-3-yl]sulfanyl]methyl][1,2,4]oxadiazol-5-yl]phenyl]carbamic acid tert-Bu ester was prepd. in 79% yield by condensation of 4-methyl-5-(thiophen-2-yl)-4H-[1,2,4]triazole-3-thiol with [3-(3-chloromethyl-[1,2,4]oxadiazol-5-yl)phenyl]carbamic acid tert-Bu ester in MeCN in the presence of K2CO3. For I: P = H, C3-7alkyl or a 3- to 8-membered ring contg. ≥1 atoms = C, N, O and S, which ring may optionally be fused with a 5- or 6-membered ring contg. ≥1 C, N, O and S; R1 = H, hydroxy, halo, nitro, C1-6-alkylhalo, OC1-6alkylhalo, C1-6alkyl, OC1-6alkyl, C2-6alkenyl, OC2-6alkenyl, C2-6alkynyl, OC2-6alkynyl, C0-6alkylC3-6cycloalkyl, etc. and a 5- or 6-membered ring contg. ≥1 C, N, O and S, wherein said ring may be substituted by ≥1 A. M1 = a bond, C1-3alkyl, C2-3alkenyl, C2-3alkynyl, C0-4alkyl(CO)C0-4alkyl, C0-3alkylOC0-3alkyl, C0-3alkyl(CO)NR5, C0-3alkyl(CO)NR5C0-3alkyl, C0-4-alkylNR5, C0-3alkylSC0-3alkyl, etc.; R2 = H, hydroxy, C0-6alkylcyano, oxo, NR5, NOR5, C1-4alkylhalo, halo, C1-4alkyl, etc. X1, X2 and X3 = CR, CO, N, NR, O and S; R = H, C0-3alkyl, halo, C0-3alkylOR5, C0-3-alkylNR5R6, C0-3alkyl(CO)OR5, C0-3alkylNR5R6 and C0-3alkylaryl; M2 = a bond, C1-3alkyl, C3-7cycloalkyl, C2-3alkenyl, C2-3alkynyl, C0-4alkyl(CO)C0-4alkyl, C0-3alkylOC0-3alkyl, etc.; R3 = H, hydroxy, C0-6alkylcyano, oxo, NR, NOR5, C1-4alkylhalo, halo, C1-4alkyl, etc. X4 = C0-4alkylR5, C0-4alkyl(NR5R6), C0-4-alkyl(NR5R6):N, NR5C0-4alkyl(NR5R6):N, NOC0-4alkyl, C1-4alkylhalo, C, O, SO, SO2 and S; Q is a 5- or 6-membered ring contg. ≥1 C, N, O and S, which group may optionally be fused with a 5- or 6-membered ring contg. ≥1 C, N, O and S and which fused ring may be substituted by ≥1 A. R4 = H, hydroxy, C0-6alkylcyano, oxo, NR5, NOR5, C1-4alkylhalo, halo, C1-4alkyl, OC1-4alkyl, OC0-6alkylaryl, etc. and a 5- or 6-membered ring contg. ≥1 atoms = C, N, O or S, wherein said ring may be substituted by ≥1 A; R5, R6 = H, OH, C1-6alkyl, etc.; A = H, OH, O, halo, nitro, C0-6alkylcyano, etc.; m = 0-4; and n = 0-3; addnl. details are given in the claims. [on SciFinder(R)]
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| 10. |
- Yngve, Ulrika, 1972-, et al.
(författare)
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Labelling of octreotide using Br-76-prosthetic groups
- 2001
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Ingår i: Journal of labelled compounds & radiopharmaceuticals. - : Wiley. - 0362-4803 .- 1099-1344. ; 44:8, s. 561-573
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Tidskriftsartikel (refereegranskat)abstract
- A method for labelling the octapeptide octreotide (D-Phe-Cys-Phe-D-TrpLys-Thr-Cys-Thr(ol)) with the positron emitting Br-76 (T-1/2 = 16 h) is presented. epsilon -Boc-protected octreotide was conjugated to N-succinimidyl 4-[Br-76]bromobenzoate 1 and N-succinimidyl 5-[Br-76]bromo-3-pyridinecarboxylate 3 using microwave heating. The conjugates 4 and 5 were isolated in 50-55% radiochemical yield after the removal of the protecting Boc-group. Compound 3 was synthesised from the corresponding trimethylstannyl-precursor in 25% radiochemical yield. The synthesis of methyl-4-[Br-76] bromobenzimidate 8 in 40% radiochemical yield from the precursor methyl -4-trimethylstannylbenzimidate is also described. Experiments were performed to react 8 with Boc-octreotide but no product was obtained. The binding-properties of Br-76-conjugates 4 and 5 to meningiomas were investigated using frozen section autoradiography. Compound 5 showed better binding properties than 4.
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